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What was the administration route of drug 'LIDOCAINE'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | Epidural | DrugAdministrationRoute | CC BY-NC | 33616459 | 19,014,130 | 2021-02 |
What was the administration route of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | Epidural | DrugAdministrationRoute | CC BY-NC | 33616459 | 19,014,130 | 2021-02 |
What was the dosage of drug 'HYALURONIDASE (HUMAN RECOMBINANT)'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | 1 MILLILITER | DrugDosageText | CC BY-NC | 33616459 | 19,360,157 | 2021-02 |
What was the dosage of drug 'LIDOCAINE'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | 0.3 MILLILITER | DrugDosageText | CC BY-NC | 33616459 | 19,360,157 | 2021-02 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | 1 MILLILITER | DrugDosageText | CC BY-NC | 33616459 | 19,360,157 | 2021-02 |
What was the dosage of drug 'SUS SCROFA PLACENTA'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | 2 MILLILITER | DrugDosageText | CC BY-NC | 33616459 | 19,360,157 | 2021-02 |
What was the outcome of reaction 'Meningitis chemical'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | Recovered | ReactionOutcome | CC BY-NC | 33616459 | 19,360,157 | 2021-02 |
What was the outcome of reaction 'Pneumocephalus'? | Chemical meningitis after cervical transforaminal epidural steroid injection: a case report.
We herein report a case of chemical meningitis that developed after cervical transforaminal steroid injection. A 49-year-old man presented with symptoms of meningitis (severe headache and neck stiffness) after cervical transforaminal steroid injection at the right C5-6 level. The injection solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). The patient developed symptoms of meningitis 2.5 hours after the cervical epidural injection. Cerebrospinal fluid (CSF) analysis was performed 1 day after the injection, and the results showed an elevated white blood cell count at 7106 cells/µL. The patient's CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that his symptoms developed 2.5 hours after the epidural injection, we believe that the patient developed chemical meningitis; therefore, he was symptomatically treated with an analgesic. Three days after the cervical transforaminal epidural injection, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Hence, the diagnosis of chemical meningitis was confirmed. Clinicians should be knowledgeable about the risk of this complication.
Introduction
In pain clinics, epidural injection is widely used to manage axial neck and back pain and radicular pain.1,2 Previous studies have shown that epidural injection is effective for treatment of radicular pain or axial pain induced by spinal stenosis or herniated discs.1,2 However, adverse effects such as neural injury, infection, cord or cerebral infarction, hematoma, and lidocaine-induced seizure can occasionally occur.3–5 Moreover, chemical meningitis is a potential adverse effect of epidural injection.6–8 This condition can cause several symptoms, such as headache, neck stiffness, fever, nausea/vomiting, and an altered mental status.6–8 In all reported cases, chemical meningitis occurred after interlaminar lumbar epidural injection.
We herein describe a patient who developed chemical meningitis after cervical transforaminal epidural steroid injection (TFESI).
Case report
A 49-year-old man underwent TFESI in the right C6 nerve root under C-arm fluoroscopic guidance for control of radicular pain induced by right C5–6 foraminal stenosis due to spondylosis in a local pain clinic. The injected solution was a mixture of lidocaine (0.3 mL), hyaluronidase (1 mL), placenta hydrolysate (2 mL), and normal saline (1 mL). Prior to the TFESI, 0.3 mL of contrast medium had been injected to determine whether the needle tip was placed at the proper location. The patient had a history of avascular necrosis of both femoral heads. In addition, he had undergone left total hip replacement for avascular necrosis of the left femoral head 3 years previously. He had undergone a single TFESI procedure of the right C6 nerve root with the same injection material 3 months previously. However, he developed no adverse effects after the previous TFESI.
About 2 hours 30 minutes after the cervical TFESI, the patient developed a severe headache. He visited the emergency department of a university hospital around 2:00 am the day after the epidural injection. Upon arrival, the patient’s body temperature was 37.7°C, and his blood pressure, pulse rate, and respiratory rate were normal. Laboratory tests showed that his white blood cell (WBC) count was elevated to 18,390 cells/µL (reference range, 4,000–10,000 cells/µL) with a neutrophil count of 80.8%, and his C-reactive protein level was elevated to 0.897 mg/dL (reference range, 0.0–0.5 mg/dL). The patient was admitted at the physical medicine and rehabilitation department. Using a numeric rating scale (0 indicating no pain and 10 indicating the worst pain imaginable), the patient gave a rating of 9 for his headache, which was aggravated in the supine position and relieved in the sitting and standing positions. The patient had also developed neck stiffness. His mental status was normal, and no motor or sensory deficits were observed. The deep tendon reflexes in the bilateral upper and lower limbs were normal. Brudzinski’s and Kernig’s signs were negative. Brain computed tomography (CT) and magnetic resonance imaging revealed no abnormalities (Figure 1). In addition, cervical spine magnetic resonance imaging revealed no specific abnormal findings other than right C5–6 foraminal stenosis. Considering the patient’s history, symptoms, and physical examination and imaging findings, we believe that he developed meningitis. Cerebrospinal fluid (CSF) analysis was performed around 1:00 pm (about 11 hours after arriving at the emergency room), revealing an elevated WBC count at 7106 cells/μL (polymorphonuclear cells, 93%; lymphocytes, 6%). Moreover, the patient’s protein and glucose concentrations were 293.95 mg/dL (reference range, 15–45 mg/dL) and 52 mg/dL (reference range, 40–70 mg/dL), respectively. The CSF was cloudy. The patient’s CSF analysis findings and symptoms did not differ from those of bacterial meningitis. However, considering that the symptoms developed 2.5 hours after the epidural injection, we believe that the patient most likely developed chemical meningitis. Dexamethasone was not administered for the treatment of chemical meningitis because the patient had a history of avascular necrosis of the femoral head; instead, only intravenous propacetamol (1 mg) was administered every 4 to 6 hours for 2 days for symptomatic treatment. If the symptoms became aggravated, we planned to start intravenous antibiotic treatment. However, the symptoms were gradually relieved. Three days after the cervical TFESI, the patient experienced complete relief from the headache and neck stiffness. A Gram stain of the CSF revealed no organisms. Additionally, fungal infection was ruled out by the CSF culture result. A follow-up CSF evaluation was conducted 6 days after the epidural injection. The following results were obtained: WBC count, 193 cells/μL (polymorphonuclear cells, 3%; lymphocytes, 73%); protein concentration, 65.38 mg/dL; and glucose concentration, 53 mg/dL. Based on the course of the patient’s symptoms and the CSF analysis findings, the diagnosis of chemical meningitis due to cervical TFESI was confirmed. The patient was discharged on the seventh day after the epidural injection.
Figure 1. Non-contrast brain computed tomography revealed no abnormalities.
Discussion
We have herein described a patient who developed chemical meningitis after TFESI. Although dexamethasone and antibiotics were not administered for treatment of the meningitis, the patient experienced complete relief from the symptoms of meningitis 3 days after the epidural injection.
The mechanism underlying the occurrence of chemical meningitis has not been clearly elucidated. However, it might be caused by allergic or hypersensitivity reactions.9 Although several reports have described chemical meningitis caused by local anesthetics after spinal anesthesia or intrathecal anesthetics and/or steroid injection,10–13 only three cases of chemical meningitis after epidural injection for pain management have been reported.6–8 In 1987, Gutknecht6 reported a case of chemical meningitis after interlaminar epidural injection at the L12–1, L4–5, and L5–S1 levels with methylprednisolone for treatment of lower back pain and lumbar radicular pain. The patient’s symptoms developed 4 hours after the epidural injection, and brain CT revealed air droplets in the subarachnoid space. In 2016, Shah et al.8 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 1.5 hours after the epidural injection of lidocaine, methylprednisolone, and betamethasone. The patient’s symptoms completely resolved 48 hours after the onset of meningitis symptoms. In 2020, Koo and Cho7 reported a case of chemical meningitis with pneumocephalus. The symptoms developed 30 minutes after lumbar interlaminar epidural injection with mepivacaine and dexamethasone. Brain CT revealed multiple small foci of air in the subarachnoid space and ventricle. Two days after initiating symptomatic treatment, the patient’s symptoms completely resolved. Because pneumocephalus was observed in these three cases,6–8 inadvertent dural puncture might have occurred during the procedure. Although there were no findings indicative of pneumocephalus in our case, there was a high risk of unintended intrathecal entry of the injected solution. In addition, a mixture of lidocaine, hyaluronidase, and placenta hydrolysate was used for cervical TFESI. Therefore, which component of the injected solution induced the chemical meningitis remains unclear.
Chemical and bacterial meningitis cannot be easily differentiated because their symptoms and laboratory findings are similar. Moreover, the CSF culture results are available after a few days.14 A previous study showed that the symptoms of bacterial meningitis usually develop 2 to 10 days after the procedure, and those of chemical meningitis develop within a few hours.15 The only significant difference between the two disorders is the duration from epidural injection to onset of symptoms. In our case, because the patient’s meningitis symptoms appeared about 2 hours 30 minutes after the cervical TFESI, we considered that our patient had chemical meningitis and therefore did not administer antibiotics. However, because the course of each disorder is not fully elucidated, clinicians should initiate empirical treatment with broad-spectrum antibiotics until the CSF culture results are available.8
In summary, we have herein reported a case of chemical meningitis that developed after TFESI. Intrathecal injection might have been conducted inadvertently. Hence, clinicians should be knowledgeable about the risk of this complication. In addition, the sensitivity and specificity of physical signs of meningeal inflammation, such as Brudzinski’s and Kernig’s signs, are not high enough to accurately rule in or rule out meningitis. Therefore, when patients complain of meningitis symptoms such as headache, neck stiffness, and nausea/vomiting after epidural injection, the occurrence of chemical meningitis should be considered even in the absence of physical signs of meningeal irritation, and CSF analysis with empirical antibiotic treatment should be initiated as soon as possible.
Ethics: The study protocol was approved by the Institutional Review Board of Yeungnam University Hospital. The patient provided written informed consent.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This work was supported by a National Research Foundation of Korea grant funded by the Korean government (grant no. NRF-2019M3E5D1A02068106).
ORCID iD: Min Cheol Chang https://orcid.org/0000-0002-7629-7213 | Recovered | ReactionOutcome | CC BY-NC | 33616459 | 19,014,130 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Acute Villitis and Intravascular Microorganisms in Fetal Vessels: A Case Report and Literature Review of an Unusual Histopathological Finding.
Optimal management of intrauterine infection to avoid serious adverse perinatal outcomes entails prompt administration of antibiotics and consideration of early delivery of the fetus to remove the focus of infection. We report an unusual case of preterm chorioamnionitis which did not improve with sensitive antibiotics, or delivery of the fetus, and ultimately required an emergency hysterectomy to save the mother's life. Interestingly, subsequent histopathological analysis of the post-hysterectomy specimen did not reveal myometrial necrosis or infectious microorganisms. The placental pathological examination, on the other hand, showed evidence of necrotising chorioamnionitis accompanied by a rarely reported lesion: acute villitis with abundant intravascular Escherichia coli, a finding which is strongly associated with fetal demise and adverse maternal outcomes.
Introduction
Acute intrauterine infection is an important contributor to adverse maternal and neonatal outcomes. Clinically, it manifests as feto-maternal tachycardia, pyrexia, uterine tenderness, maternal leucocytosis and/or foul-smelling purulent fluid or discharge from the cervical os.1 Suspected acute intrauterine infection can be confirmed in pregnant women by objective pre- and postnatal laboratory findings, including pathological examination of the placenta.2 Histologically, acute intrauterine infection comprises a: 1) maternal inflammatory response (MIR) demonstrated by the presence of neutrophilic infiltration in chorion and/or amnion in the fetal membranes and/or in the chorionic plate (acute chorioamnionitis); with or without a 2) fetal inflammatory response (FIR) demonstrated by the presence of neutrophilic infiltration in umbilical vessels with or without Wharton substance involvement and infiltration in chorionic plate vessels.3,4
Acute villitis, defined as the presence of neutrophilic infiltration in fetal villous capillaries and stroma, is an uncommon histological entity which may occur in isolation or accompanied by chorioamnionitis, and normally indicates severe fetal sepsis. Rarely, it may be accompanied by an abundance of microorganisms in the fetal vessels of the chorionic villi.5,6
In this paper, we report a rare case of severe maternal sepsis caused by necrotising preterm chorioamnionitis with acute villitis and intravascular microorganisms which only responded to hysterectomy.
Case Report
A nulliparous woman of childbearing age with no pre-existing comorbidities was found to have an incidental large cervical funnel in an otherwise normal cervix (42 mm long) when she attended her regular anomaly scan at 20 weeks. Up to that point, she had not experienced any antenatal complications with normal booking bloods and low-risk results from the combined first trimester screening test for chromosomal abnormalities. A follow-up transvaginal scan two weeks later revealed the cervix had significantly shortened to 4-5 mm with a large funnel and intra-amniotic sludge, and the patient was offered a rescue cerclage (Figure 1). Unfortunately, as the suture was being secured, premature rupture of the membranes was identified and the procedure was abandoned. She was then started on a seven-day prophylactic course of erythromycin and received steroids cover for fetal lung maturation. Following completion of her antibiotics course, the patient remained clinically well with normal-range inflammatory markers for another week. Microbial high-vaginal swabs analysis did not reveal any pathogenic fungal or bacterial growth. When the metabolomic fingerprint of the cervicovaginal fluid was further analysed by Raman Spectroscopy, no evidence of altered carbohydrate metabolism normally exhibited by the subclinical overgrowth of preterm birth-associated anaerobic bacteria was identified.7
Figure 1. Transvaginal ultrasound of the cervix in longitudinal view at 22 weeks of gestation. The cervix was 4.58 mm long (yellow callipers), with a large funnel and intra-amniotic sludge.
At 24 weeks and 4 days, the patient suddenly felt unwell, and became septic with significantly raised venous lactate levels (>6 mmol/L). Fetal demise was confirmed at this point. Despite high-flow oxygen, intravenous broad-spectrum antibiotics and aggressive fluid resuscitation, the patient continued to deteriorate and became hypotensive, tachycardic, hypoxic and pyrexial. A decision to expedite delivery was made, and a hysterotomy under general anaesthesia was performed on the same day. The placenta was sent for histopathologic examination and no delay in fixing the sample at delivery theatre was noted.
Intraoperatively, the patient remained haemodynamically unstable requiring a high dose of vasopressors and support for ventilation. The patient was then transferred to critical care for management of her sepsis. Antibiotics were escalated to meropenem and clindamycin as preliminary blood cultures, and placental and fetal swabs reported the presence of Gram negative microorganisms later confirmed to be Escherichia coli. By the second day post-hysterotomy, the patient continued to develop signs of multi-organ failure. An urgent chest, abdomen and pelvis computed tomography was performed to rule out a collection and failed to identify a source of sepsis. In view of the patient’s worsening condition, and on suspicion of myometrial necrosis, a hysterectomy with conservation of tubes and ovaries was performed 36 hours after delivery of the fetus. Soon after the surgery, the patient experienced a marked clinical improvement and continued to recover in the following weeks.
Thorough histological analysis of the uterus, however, did not identify any evidence of retained products of conception, myometrial necrosis or infectious microorganisms, only interstitial haemorrhage with focal and perivascular acute inflammatory cells close to the low uterine segment incision. The analysis of the placenta, on the other hand, confirmed the diagnosis of acute necrotising chorioamnionitis (MIR = stage 3, grade 2; FIR = stage 3, grade 2) associated with acute villitis and numerous fusiform Gram negative microorganisms located within the large number of fetal vessels from stem to terminal villi, which were later confirmed to be Escherichia coli (Figure 2). No fetal autopsy was performed as per parents’ wishes.
Figure 2. A, The microscopic evaluation of the placenta delivered at 24 weeks and 4 days of gestation complicated by a maternal septic shock requiring hysterectomy 36 hours after delivery: placental villi showing villitis (stars) associated to the presence of bacterial organisms in fetal vessels (arrows) (H&E × 20). B, Gram Twort stain shows red bacilli filling the fetal blood vessels in villi (arrows × 60). The microorganisms were located within the large number of fetal placental vessels, involving all villous subdivisions of the villous tree ramifications. Affected vessels were tightly filled with bacteria.
Discussion and Conclusion
The presence of bacteria within the placental fetal capillaries constitutes a rarely reported histological finding.5,6,8 A comprehensive electronic and hand search performed in Medline via OvidSP, Scopus and Web of Science from inception to May 2020 only yielded three case reports5,8 and one short case series6 (Appendix 1: Figure A1).
In all the cases published, including the one reported in this paper, the presence of intravascular microorganisms in the fetal capillaries of the chorionic villi has been associated, without exception, with second-trimester fetal demise (Table 1). The analysis of the placenta provided key information about the timing of the infection and the causative agents. The presence of bacterial microorganisms in the fetal vasculature was accompanied by acute villitis, an atypical inflammatory fetal response (Table 1). Evidence of neutrophil infiltration in the fetal capillaries and chorionic villi demonstrates that the bacteria were present in fetal circulation while the fetus was still alive rather than postnatally or due to placental contamination.4,6,9 The degree of fetal inflammatory response seen in these placentas suggests that the fetal septicaemia was severe enough to cause fetal death. Placental analysis using appropriate immunohistochemistry and PCR testing also enabled to identify the infective agents in almost all the cases reported even when urine, blood and placenta microbiology cultures had been inconclusive.6 The leading species were Escherichia coli and Group B Streptococcus which have well-documented associations with ascending polymicrobial intrauterine infections10 (Table 1).
Table 1. Reported Cases of Placental Fetal Intravascular Microorganisms.
Study Gestational Age Bacteria Clinical Outcomes Histological Findings
Maternal Fetal Maternal Fetal
Sheikh et al.11 18 weeks (n = 1) Klebsiella pneumoniae Sepsis Death Chorioamnionitis Acute villitis
Matoso et al.5 17 weeks
(n = 1) GBS Sepsis Death Chorioamnionitis Acute villitis
Bae et al.8 21 weeks
(n = 1) GBS Sepsis Death Chorioamnionitis Acute villitis
Schubert et al.6 16-27 weeks (n = 13) E.coli (n = 8)
GBS
(n = 3)
GPC
(n = 2) Sepsis
(n = 9)
ICU admission
(n = 2)
Death (n = 1) Death (n = 13) Chorioamnionitis
(n = 11) Acute villitis
(n = 13)
Present case 24 weeks (n = 1) E.coli Sepsis
ICU admission
Hysterectomy Death Chorioamnionitis Acute villitis
GBS: Group B Streptococcus, E.coli: Escherichia coli, GPC: Gram positive cocci, ICU: intensive care unit.
Maternal sepsis secondary to chorioamnionitis is a rare occurrence even in the context of premature rupture of membranes with some studies quoting rates of less than 1%. Admission to intensive unit remains uncommon, and prognosis is generally good.10,12 However, when there is presence of intravascular microorganisms in the placental villi, maternal morbidity and mortality rate have been noticed to be significantly higher than any other intrauterine infection.
In over seventy-five percent of all the cases reported (n=13), women became septic; three of whom required intensive-unit support (23%), one underwent hysterectomy and one died (8%, Table 1).
The few available cases of acute villitis and intravascular microorganisms identified in the literature were reported in high-income countries (Table 1). In these settings, peripartum hysterectomies are rarely performed (approximately 0.7:1,000 pregnancies), with the leading cause being morbidly adherent placenta rather than chorioamnionitis. In our tertiary maternity unit which oversees 7,000 births per year, for example, this is one of the first times uterine, placental and clinical outcomes have been triangulated in the context of a life-threatening intrauterine infection given the rarity of performing peripartum hysterectomies for puerperal sepsis.
On the contrary, in low-income countries, feto-maternal sepsis remains a relatively usual indication for hysterectomies, which along with uterine rupture and intractable postpartum haemorrhage complicates at least 2.8 every 1,000 pregnancies.13–15 However, histopathological analysis of the uterus, placenta and fetus remains a relatively uncommon event in these settings which limits our understanding of the true incidence of acute villitis associated with intravascular microorganisms and leads to potential reporting bias.16
Traditionally, in high-income countries, the gold-standard clinical management of intrauterine infection comprises broad-spectrum antibiotics and removing the focus of infection by early delivery of the fetus.2 In the case we report, the patient failed to respond to conventional treatment, but greatly improved after the uterus was removed. A thorough histopathological analysis of the uterus, however, did not reveal any evidence of uterine infection. Although it remains a possibility that sampling may have missed a focus of persistent infection in the uterus, 14 extensive samples taken from the cervix, the right and left cornua, the uterine lower and anterior aspects, the fundus, and the included resection margins did not show any fungal or bacterial infection. As no samples were taken from the uterine veins at the parametrial margin of resection, septic venous thrombophlebitis could not be completely ruled out as a persistent focus of infection. However, it is unlikely to have been the cause for the patient’s acute decompensation as no signs of thrombosis were identified during the surgery which was performed jointly by three senior consultant gynaecologists and one senior obstetrician.
Based on the lack of response to conventional treatment, the patient’s clinical evolution after hysterectomy and the uterine and placental findings, we hypothesised that the uterus likely had been housing a large array of inflammatory cytokines secondary to the severe maternal immune response mounted against the feto-placental infection. Once this highly-active inflammatory milieu was removed during the hysterectomy, the patient made a significant clinical improvement.
As demonstrated by our case and supported by previous literature,5,6,8 acute villitis accompanied by the presence of intravascular microorganisms in fetal vessels is associated without exception with fetal demise, and it is more likely to be found in the context of intractable maternal sepsis. The correlation between histopathological findings and adverse feto-maternal outcomes supports a detailed histological analysis of the placenta in cases of severe acute intrauterine infection which do not respond to first-line management. Such analysis is likely not only to provide a better understanding of the origin, timing and aetiology of the inflammatory process, but also to inform current and subsequent obstetric management of these patients.
Appendix 1: Search strategy for systematic review on human cases reporting on bacterial organisms filling the intravascular spaces of the chorionic villi
An electronic search in Medline via OvidSP, Scopus and Web of Science was performed from inception to May 2020 to identify any case and/or series cases written in English and Spanish which reported on the presence of bacteria in human fetal capillaries. We employed a combination of relevant MeSH, keywords and synonyms such as acute villitis, bacteria, chorioamnionitis and fetal intravascular microorganisms. The scoping search was supplemented by hand-searching of references and perusing of grey literature.
Database: Ovid Medline
<1946 to Present>
Search Strategy: *Chorioamnionitis/ or *Pregnancy/ or *Adult/ or *Humans/ or Premature Birth/ or *Pregnancy Complications, Infectious/ or *Placenta/ or “acute villitis”.mp. or *Placenta Diseases/ (107427)
*Bacteria, Aerobic/ or *Gram-Negative Bacteria/ or *Bacteria/ or bacteria.mp. or *Bacteria, Anaerobic/ or *Gram-Positive Bacteria/ (500580)
chorioamnionitis.mp. or *Chorioamnionitis/ (4986)
*Fetus/ or *Fetal Diseases/ or *Placenta/ or "fetal intravascular organism".mp. or *Chorionic Villi/ (90274)
*Adult/ or *Chorioamnionitis/ or *Sepsis/ or *Fetal Membranes, Premature Rupture/ or *Pregnancy/ or *Fetal Diseases/ or *Humans/ or "fetal sepsis".mp. or *Pregnancy Complications, Infectious/ (124620)
"placenta".mp. or *Placenta/ or *Placenta Diseases/ (84976)
1 and 2 and 3 and 4 and 5 and 6 (19)
Total n=19
Database: Scopus
<1960 to Present>
Search Strategy:
------------------------
acute villitis AND bacteria AND chorioamnionitis AND fetal intravascular organism* AND fetal sepsis AND placenta
Total n=1
Database: Web of Science
<1846 to Present>
Search Strategy:
------------------------
acute villitis AND bacteria AND chorioamnionitis AND fetal intravascular organism* AND fetal sepsis AND placenta
Total n=2
The initial electronic search yielded 19 results from Medline, two from Web of Science, one from Scopus and two from the citation search adding up to a total of 24 hits, one of which was excluded for duplication.6 The titles and abstracts of the remaining 23 studies were screened for inclusion, out of which 18 were removed for not meeting the inclusion criteria. Five papers were then fully read, and one further study was excluded for not reporting specifically on the presence of microorganisms in the fetal capillaries of the placenta.17 The final list included three case reports and a short case-series.5,6,8
Figure A1. The PRISMA flow chart shows the methodology for the selection of cases reporting on bacterial organisms filling the intravascular spaces of the chorionic villi.
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.
ORCID iD: Martyna Trzeszcz https://orcid.org/0000-0002-9971-1093 | CLINDAMYCIN, MEROPENEM | DrugsGivenReaction | CC BY | 33617361 | 19,394,455 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple organ dysfunction syndrome'. | Acute Villitis and Intravascular Microorganisms in Fetal Vessels: A Case Report and Literature Review of an Unusual Histopathological Finding.
Optimal management of intrauterine infection to avoid serious adverse perinatal outcomes entails prompt administration of antibiotics and consideration of early delivery of the fetus to remove the focus of infection. We report an unusual case of preterm chorioamnionitis which did not improve with sensitive antibiotics, or delivery of the fetus, and ultimately required an emergency hysterectomy to save the mother's life. Interestingly, subsequent histopathological analysis of the post-hysterectomy specimen did not reveal myometrial necrosis or infectious microorganisms. The placental pathological examination, on the other hand, showed evidence of necrotising chorioamnionitis accompanied by a rarely reported lesion: acute villitis with abundant intravascular Escherichia coli, a finding which is strongly associated with fetal demise and adverse maternal outcomes.
Introduction
Acute intrauterine infection is an important contributor to adverse maternal and neonatal outcomes. Clinically, it manifests as feto-maternal tachycardia, pyrexia, uterine tenderness, maternal leucocytosis and/or foul-smelling purulent fluid or discharge from the cervical os.1 Suspected acute intrauterine infection can be confirmed in pregnant women by objective pre- and postnatal laboratory findings, including pathological examination of the placenta.2 Histologically, acute intrauterine infection comprises a: 1) maternal inflammatory response (MIR) demonstrated by the presence of neutrophilic infiltration in chorion and/or amnion in the fetal membranes and/or in the chorionic plate (acute chorioamnionitis); with or without a 2) fetal inflammatory response (FIR) demonstrated by the presence of neutrophilic infiltration in umbilical vessels with or without Wharton substance involvement and infiltration in chorionic plate vessels.3,4
Acute villitis, defined as the presence of neutrophilic infiltration in fetal villous capillaries and stroma, is an uncommon histological entity which may occur in isolation or accompanied by chorioamnionitis, and normally indicates severe fetal sepsis. Rarely, it may be accompanied by an abundance of microorganisms in the fetal vessels of the chorionic villi.5,6
In this paper, we report a rare case of severe maternal sepsis caused by necrotising preterm chorioamnionitis with acute villitis and intravascular microorganisms which only responded to hysterectomy.
Case Report
A nulliparous woman of childbearing age with no pre-existing comorbidities was found to have an incidental large cervical funnel in an otherwise normal cervix (42 mm long) when she attended her regular anomaly scan at 20 weeks. Up to that point, she had not experienced any antenatal complications with normal booking bloods and low-risk results from the combined first trimester screening test for chromosomal abnormalities. A follow-up transvaginal scan two weeks later revealed the cervix had significantly shortened to 4-5 mm with a large funnel and intra-amniotic sludge, and the patient was offered a rescue cerclage (Figure 1). Unfortunately, as the suture was being secured, premature rupture of the membranes was identified and the procedure was abandoned. She was then started on a seven-day prophylactic course of erythromycin and received steroids cover for fetal lung maturation. Following completion of her antibiotics course, the patient remained clinically well with normal-range inflammatory markers for another week. Microbial high-vaginal swabs analysis did not reveal any pathogenic fungal or bacterial growth. When the metabolomic fingerprint of the cervicovaginal fluid was further analysed by Raman Spectroscopy, no evidence of altered carbohydrate metabolism normally exhibited by the subclinical overgrowth of preterm birth-associated anaerobic bacteria was identified.7
Figure 1. Transvaginal ultrasound of the cervix in longitudinal view at 22 weeks of gestation. The cervix was 4.58 mm long (yellow callipers), with a large funnel and intra-amniotic sludge.
At 24 weeks and 4 days, the patient suddenly felt unwell, and became septic with significantly raised venous lactate levels (>6 mmol/L). Fetal demise was confirmed at this point. Despite high-flow oxygen, intravenous broad-spectrum antibiotics and aggressive fluid resuscitation, the patient continued to deteriorate and became hypotensive, tachycardic, hypoxic and pyrexial. A decision to expedite delivery was made, and a hysterotomy under general anaesthesia was performed on the same day. The placenta was sent for histopathologic examination and no delay in fixing the sample at delivery theatre was noted.
Intraoperatively, the patient remained haemodynamically unstable requiring a high dose of vasopressors and support for ventilation. The patient was then transferred to critical care for management of her sepsis. Antibiotics were escalated to meropenem and clindamycin as preliminary blood cultures, and placental and fetal swabs reported the presence of Gram negative microorganisms later confirmed to be Escherichia coli. By the second day post-hysterotomy, the patient continued to develop signs of multi-organ failure. An urgent chest, abdomen and pelvis computed tomography was performed to rule out a collection and failed to identify a source of sepsis. In view of the patient’s worsening condition, and on suspicion of myometrial necrosis, a hysterectomy with conservation of tubes and ovaries was performed 36 hours after delivery of the fetus. Soon after the surgery, the patient experienced a marked clinical improvement and continued to recover in the following weeks.
Thorough histological analysis of the uterus, however, did not identify any evidence of retained products of conception, myometrial necrosis or infectious microorganisms, only interstitial haemorrhage with focal and perivascular acute inflammatory cells close to the low uterine segment incision. The analysis of the placenta, on the other hand, confirmed the diagnosis of acute necrotising chorioamnionitis (MIR = stage 3, grade 2; FIR = stage 3, grade 2) associated with acute villitis and numerous fusiform Gram negative microorganisms located within the large number of fetal vessels from stem to terminal villi, which were later confirmed to be Escherichia coli (Figure 2). No fetal autopsy was performed as per parents’ wishes.
Figure 2. A, The microscopic evaluation of the placenta delivered at 24 weeks and 4 days of gestation complicated by a maternal septic shock requiring hysterectomy 36 hours after delivery: placental villi showing villitis (stars) associated to the presence of bacterial organisms in fetal vessels (arrows) (H&E × 20). B, Gram Twort stain shows red bacilli filling the fetal blood vessels in villi (arrows × 60). The microorganisms were located within the large number of fetal placental vessels, involving all villous subdivisions of the villous tree ramifications. Affected vessels were tightly filled with bacteria.
Discussion and Conclusion
The presence of bacteria within the placental fetal capillaries constitutes a rarely reported histological finding.5,6,8 A comprehensive electronic and hand search performed in Medline via OvidSP, Scopus and Web of Science from inception to May 2020 only yielded three case reports5,8 and one short case series6 (Appendix 1: Figure A1).
In all the cases published, including the one reported in this paper, the presence of intravascular microorganisms in the fetal capillaries of the chorionic villi has been associated, without exception, with second-trimester fetal demise (Table 1). The analysis of the placenta provided key information about the timing of the infection and the causative agents. The presence of bacterial microorganisms in the fetal vasculature was accompanied by acute villitis, an atypical inflammatory fetal response (Table 1). Evidence of neutrophil infiltration in the fetal capillaries and chorionic villi demonstrates that the bacteria were present in fetal circulation while the fetus was still alive rather than postnatally or due to placental contamination.4,6,9 The degree of fetal inflammatory response seen in these placentas suggests that the fetal septicaemia was severe enough to cause fetal death. Placental analysis using appropriate immunohistochemistry and PCR testing also enabled to identify the infective agents in almost all the cases reported even when urine, blood and placenta microbiology cultures had been inconclusive.6 The leading species were Escherichia coli and Group B Streptococcus which have well-documented associations with ascending polymicrobial intrauterine infections10 (Table 1).
Table 1. Reported Cases of Placental Fetal Intravascular Microorganisms.
Study Gestational Age Bacteria Clinical Outcomes Histological Findings
Maternal Fetal Maternal Fetal
Sheikh et al.11 18 weeks (n = 1) Klebsiella pneumoniae Sepsis Death Chorioamnionitis Acute villitis
Matoso et al.5 17 weeks
(n = 1) GBS Sepsis Death Chorioamnionitis Acute villitis
Bae et al.8 21 weeks
(n = 1) GBS Sepsis Death Chorioamnionitis Acute villitis
Schubert et al.6 16-27 weeks (n = 13) E.coli (n = 8)
GBS
(n = 3)
GPC
(n = 2) Sepsis
(n = 9)
ICU admission
(n = 2)
Death (n = 1) Death (n = 13) Chorioamnionitis
(n = 11) Acute villitis
(n = 13)
Present case 24 weeks (n = 1) E.coli Sepsis
ICU admission
Hysterectomy Death Chorioamnionitis Acute villitis
GBS: Group B Streptococcus, E.coli: Escherichia coli, GPC: Gram positive cocci, ICU: intensive care unit.
Maternal sepsis secondary to chorioamnionitis is a rare occurrence even in the context of premature rupture of membranes with some studies quoting rates of less than 1%. Admission to intensive unit remains uncommon, and prognosis is generally good.10,12 However, when there is presence of intravascular microorganisms in the placental villi, maternal morbidity and mortality rate have been noticed to be significantly higher than any other intrauterine infection.
In over seventy-five percent of all the cases reported (n=13), women became septic; three of whom required intensive-unit support (23%), one underwent hysterectomy and one died (8%, Table 1).
The few available cases of acute villitis and intravascular microorganisms identified in the literature were reported in high-income countries (Table 1). In these settings, peripartum hysterectomies are rarely performed (approximately 0.7:1,000 pregnancies), with the leading cause being morbidly adherent placenta rather than chorioamnionitis. In our tertiary maternity unit which oversees 7,000 births per year, for example, this is one of the first times uterine, placental and clinical outcomes have been triangulated in the context of a life-threatening intrauterine infection given the rarity of performing peripartum hysterectomies for puerperal sepsis.
On the contrary, in low-income countries, feto-maternal sepsis remains a relatively usual indication for hysterectomies, which along with uterine rupture and intractable postpartum haemorrhage complicates at least 2.8 every 1,000 pregnancies.13–15 However, histopathological analysis of the uterus, placenta and fetus remains a relatively uncommon event in these settings which limits our understanding of the true incidence of acute villitis associated with intravascular microorganisms and leads to potential reporting bias.16
Traditionally, in high-income countries, the gold-standard clinical management of intrauterine infection comprises broad-spectrum antibiotics and removing the focus of infection by early delivery of the fetus.2 In the case we report, the patient failed to respond to conventional treatment, but greatly improved after the uterus was removed. A thorough histopathological analysis of the uterus, however, did not reveal any evidence of uterine infection. Although it remains a possibility that sampling may have missed a focus of persistent infection in the uterus, 14 extensive samples taken from the cervix, the right and left cornua, the uterine lower and anterior aspects, the fundus, and the included resection margins did not show any fungal or bacterial infection. As no samples were taken from the uterine veins at the parametrial margin of resection, septic venous thrombophlebitis could not be completely ruled out as a persistent focus of infection. However, it is unlikely to have been the cause for the patient’s acute decompensation as no signs of thrombosis were identified during the surgery which was performed jointly by three senior consultant gynaecologists and one senior obstetrician.
Based on the lack of response to conventional treatment, the patient’s clinical evolution after hysterectomy and the uterine and placental findings, we hypothesised that the uterus likely had been housing a large array of inflammatory cytokines secondary to the severe maternal immune response mounted against the feto-placental infection. Once this highly-active inflammatory milieu was removed during the hysterectomy, the patient made a significant clinical improvement.
As demonstrated by our case and supported by previous literature,5,6,8 acute villitis accompanied by the presence of intravascular microorganisms in fetal vessels is associated without exception with fetal demise, and it is more likely to be found in the context of intractable maternal sepsis. The correlation between histopathological findings and adverse feto-maternal outcomes supports a detailed histological analysis of the placenta in cases of severe acute intrauterine infection which do not respond to first-line management. Such analysis is likely not only to provide a better understanding of the origin, timing and aetiology of the inflammatory process, but also to inform current and subsequent obstetric management of these patients.
Appendix 1: Search strategy for systematic review on human cases reporting on bacterial organisms filling the intravascular spaces of the chorionic villi
An electronic search in Medline via OvidSP, Scopus and Web of Science was performed from inception to May 2020 to identify any case and/or series cases written in English and Spanish which reported on the presence of bacteria in human fetal capillaries. We employed a combination of relevant MeSH, keywords and synonyms such as acute villitis, bacteria, chorioamnionitis and fetal intravascular microorganisms. The scoping search was supplemented by hand-searching of references and perusing of grey literature.
Database: Ovid Medline
<1946 to Present>
Search Strategy: *Chorioamnionitis/ or *Pregnancy/ or *Adult/ or *Humans/ or Premature Birth/ or *Pregnancy Complications, Infectious/ or *Placenta/ or “acute villitis”.mp. or *Placenta Diseases/ (107427)
*Bacteria, Aerobic/ or *Gram-Negative Bacteria/ or *Bacteria/ or bacteria.mp. or *Bacteria, Anaerobic/ or *Gram-Positive Bacteria/ (500580)
chorioamnionitis.mp. or *Chorioamnionitis/ (4986)
*Fetus/ or *Fetal Diseases/ or *Placenta/ or "fetal intravascular organism".mp. or *Chorionic Villi/ (90274)
*Adult/ or *Chorioamnionitis/ or *Sepsis/ or *Fetal Membranes, Premature Rupture/ or *Pregnancy/ or *Fetal Diseases/ or *Humans/ or "fetal sepsis".mp. or *Pregnancy Complications, Infectious/ (124620)
"placenta".mp. or *Placenta/ or *Placenta Diseases/ (84976)
1 and 2 and 3 and 4 and 5 and 6 (19)
Total n=19
Database: Scopus
<1960 to Present>
Search Strategy:
------------------------
acute villitis AND bacteria AND chorioamnionitis AND fetal intravascular organism* AND fetal sepsis AND placenta
Total n=1
Database: Web of Science
<1846 to Present>
Search Strategy:
------------------------
acute villitis AND bacteria AND chorioamnionitis AND fetal intravascular organism* AND fetal sepsis AND placenta
Total n=2
The initial electronic search yielded 19 results from Medline, two from Web of Science, one from Scopus and two from the citation search adding up to a total of 24 hits, one of which was excluded for duplication.6 The titles and abstracts of the remaining 23 studies were screened for inclusion, out of which 18 were removed for not meeting the inclusion criteria. Five papers were then fully read, and one further study was excluded for not reporting specifically on the presence of microorganisms in the fetal capillaries of the placenta.17 The final list included three case reports and a short case-series.5,6,8
Figure A1. The PRISMA flow chart shows the methodology for the selection of cases reporting on bacterial organisms filling the intravascular spaces of the chorionic villi.
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.
ORCID iD: Martyna Trzeszcz https://orcid.org/0000-0002-9971-1093 | CLINDAMYCIN, MEROPENEM | DrugsGivenReaction | CC BY | 33617361 | 19,414,928 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Very Delayed Acute Hepatitis after Pembrolizumab Therapy for Advanced Malignancy: How Long Should We Watch?
Immune checkpoint inhibitors (ICIs) have led to major therapeutic advances in the management of malignancy. Despite promising outcomes for some cancers, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs). These may affect a wide array of organ systems. In particular, ICI-induced hepatitis is diagnostically challenging given its variable natural history and clinical manifestations. The onset of ICI-induced hepatitis often occurs between 6 and 14 weeks after treatment initiation and rarely exhibits delayed presentations or manifests after treatment cessation. We present a case of very delayed-onset ICI-induced hepatitis, stressing the importance of long-term surveillance for immune-indued hepatitis in patients initiated on ICIs even long after treatment cessation.
1. Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the prognosis of patients with some cancers. These novel agents augment the immune system by downregulating inhibitors of the anti-cancer immune response, including: cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), program cell death receptor 1 (PD-1) and its ligand—programmed cell death ligand 1 (PD-L1) [1]. Despite promising clinical outcomes, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs) due to the induction of autoimmunity. IrAEs have the potential to affect a wide range of organ systems, commonly including: dermatological (skin rashes), endocrine, gastrointestinal and hepatic. As ICI therapy becomes more widespread in cancer management, IrAEs are becoming more common, including immune-induced hepatitis. We present a case of very delayed-onset ICI-induced hepatitis that occurred 7 months post-treatment cessation, thereby highlighting the importance of prolonged monitoring for an acute hepatitis with careful consideration of its diagnostic and treatment nuances.
2. Case Report
Written informed consent has been obtained from the patient to publish this paper.
A 78-year-old female with stage IIIC breast cancer presented with subacute onset of jaundice. Her breast cancer had been treated with pembrolizumab for 5 months and ceased 7 months prior to presentation. She developed a prodrome of progressive fatigue and anorexia over 2 weeks. There were no recent medication changes other than oral mesalazine, which was commenced 3 months prior due to a new diagnosis of unspecified left-sided colitis confirmed during colonoscopy (possibly immune mediated).
She was diagnosed with stage IIIB triple negative inflammatory breast cancer in 2015. This was treated with neoadjuvant chemotherapy and surgery with subsequent adjuvant radiotherapy. Approximately 12 months prior to her presentation, she developed a locally advanced right breast recurrence requiring neoadjuvant chemotherapy and PD-1 inhibitor (pembrolizumab) prior to double mastectomy.
Initial biochemistry revealed a severe transaminitis. Her bilirubin was 199 μmol/L (<20 μmol/L) with an alanine transferase (ALT) of 1519 U/L (<40 U/L), gamma-glutamyltransferase (GGT) of 440 U/L (<60U/L) and alkaline phosphatase (ALP) of 208 (<130 U/L). She had preserved synthetic function with an international normalised ratio (INR) of 1.0 (<1.2) and an albumin of 31 g/L (34–54 g/L). Her viral hepatitis serology including hepatitis E virus, cytomegalovirus and Epstein–Barr virus was negative. A liver autoantibody screen was non-contributory. Her immunoglobulin G (IgG) titre was 9.4g/L (7–16 g/L). A liver ultrasound and subsequent magnetic resonance cholangiopancreatography (MRCP) showed no structural abnormalities or metastatic disease.
The patient was admitted for 2 weeks with a provisional diagnosis of drug-induced liver injury (DILI) secondary to mesalazine or immunotherapy. Mesalazine was ceased and she was managed expectantly. On Day 5, her liver function tests (LFTs) worsened, her bilirubin peaked at 205 μmol/L with an ALT of 1543 U/L. A liver biopsy revealed pan-lobular hepatitis with scattered apoptic hepatocytes, necro-inflammatory foci, lymphocytosis and foci of interface activity consistent with ICI-induced hepatitis (Figure 1). Given the biopsy results, she was initiated on 50 mg of oral prednisolone (1 mg/kg/day) to minimise glucocorticoid-related side effects. The patient’s clinical and biochemical status improved with a daily downtrend in LFTs, and resolution of her fatigue and anorexia (Figure 2). She was subsequently discharged with regular LFT monitoring and a slow glucocorticoid taper.
Considering her biopsy results and rapid resolution of liver function whilst on glucocorticoid therapy, a diagnosis of delayed immune-induced hepatitis secondary to pembrolizumab was made.
3. Discussion
The clinical manifestations and natural history of ICI-induced hepatitis are heterogenous. Acute hepatitis occurs in 2–10% of patients on ICI therapy, which typically presents as an asymptomatic transaminitis [2,3]. Occasionally, patients may develop a rapidly progressive acute hepatitis and even fulminant liver failure associated with significant morbidity and mortality [4,5]. Contrary to the usual timeframe for disease onset, our patient developed ICI-induced hepatitis 7 months post-treatment cessation. Only one other author has reported a case of delayed ICI-induced hepatitis occurring 8 months post-nivolumab cessation [6]. Delayed-onset immune-induced hepatitis after treatment cessation is rare and most reported cases occur during active treatment—between 6 and 14 weeks after treatment initiation [7]. Hence, this case serves as a reminder to strictly monitor liver function monitoring up to 12 months post-treatment cessation to detect an evolving hepatitis.
ICI-induced hepatitis can be pathologically difficult to differentiate from autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). Contrasting with AIH, auto-antibodies including anti-nuclear and anti-smooth muscle antibodies may be negative in ICI-induced hepatitis. Similarly, serum IgG levels are normal or slightly elevated in ICI-induced hepatitis as exemplified by our case [2]. Liver biopsy is often not required in suspected ICI-induced hepatitis and is only indicated to exclude other causes of acute hepatitis or quantify the degree of hepatocellular injury. Biopsy findings in ICI-induced hepatitis are variable. Most commonly, panlobular hepatitis is observed in approximately 70% of cases, typified by scattered focal necrosis and acidophilic bodies [8]. Histopathological factors which differentiate AIH and DILI from ICP-hepatitis are summarised in Table 1 [2]. In our case, liver biopsy demonstrated classical features of ICI-induced hepatitis without features of AIH or DILI from mesalazine. The cellular infiltrate was suggestive of ICI-related pathology given a lymphocytic predominance without plasmacytosis nor eosinophilia. Detailed knowledge around the pathological and biochemical intricacies of ICI-induced hepatitis can greatly assist with prompt diagnosis and treatment.
Management of ICI-induced hepatitis is based on the Common Terminology Criteria for Adverse Events (CTCAE), which grades severity of disease from 1–4 [3]. Our patient presented with grade 4 hepatitis which was glucocorticoid responsive. Current guidelines advocate for prompt glucocorticoid treatment with methylprednisolone or equivalent at 1–2 mg/kg/day for three days (up to 1 g/day), followed by prednisolone 1–2 mg/kg/day over 4 weeks. In steroid-refractory cases, the introduction of mycophenolate or azathioprine is prudent. Permanent discontinuation of ICI therapy is recommended in grade 3–4 hepatitis [3,9]. Corticosteroid therapy in ICI-induced hepatitis is contentious. Spontaneous improvement in LFTs can occur with observation and low doses of corticosteroids may be sufficient to control disease [5]. Our patient was promptly commenced on prednisolone therapy at a relatively low starting dose compared with pulsed methylprednisolone with rapid clinical response and excellent efficacy. Our case supports that LFT resolution is achievable with a lower dose glucocorticoid, thereby reducing glucocorticoid-related side effects. Further high-quality randomised-controlled studies are required to assess optimal management strategies for ICI-induced hepatitis.
Delayed-onset IrAEs of any organ system are underrecognised and clinical vigilance is critical even after treatment cessation [10]. The median interval to delayed-onset IrAE diagnosis is 6 months post-immunotherapy cessation (IQR 3–28 months) [10]. Currently, there is a paucity of evidence on delayed-onset IrAEs due to limited follow up periods and incompleteness of IrAE reporting in immuno-oncology clinical trials [11]. Best practice guidelines allude to monitoring for delayed-onset IrAEs up to 12 months after treatment discontinuation [9]. However, late-onset IrAEs are difficult to predict with available investigations and are challenging to prevent. Surveillance for IrAEs should be individualised based on a patient’s risk profile for developing IrAEs. A patient’s risk for IrAEs is increased in the presence of patient and treatment factors including: pre-existing connective tissue, vasculitic or auto-immune disease, and combination ICI usage [1]. The utility of active surveillance strategies for delayed-onset IrAEs remains an area of active research with no evidence-based algorithms available.
4. Conclusions
ICIs are becoming an integral part of cancer therapy, and monitoring for adverse events requires awareness from all physicians and not just oncologists. This case pertinently emphasises the importance of long-term surveillance for immune-induced hepatitis in patients initiated on ICI therapy. Attentive appraisal of symptoms, signs and investigations is required for prompt diagnosis of ICI-induced hepatitis allowing for the timely introduction of therapy. Systemic treatment is nuanced and further high-quality evidence is required to guide optimal therapy. We advocate for individualised surveillance strategies for delayed-onset IrAEs up to 12-months after treatment cessation. However, stringent evidence-based surveillance protocols remains an area of ongoing development.
5. Clinical Practice Points
Delayed-onset ICI-induced hepatitis can occur up to 12 months post-treatment cessation;
Autoimmune biomarkers are often negative in ICI-induced hepatitis and plasmacytosis or eosinophilia is uncommon in the biopsy cellular infiltrate;
Low-dose glucocorticoid therapy may be warranted in select ICI-induced hepatitis patients, but further randomized control studies are required to assess optimal glucocorticoid dosing;
Routine monitoring for delayed-onset IrAEs including liver function should be individualised and can extend up to 12 months post-treatment cessation.
Author Contributions
T.P.—case analysis and writing. K.P., L.L., V.K., A.A. and S.P.—review and editing of subsequent drafts. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Histologic examination of liver lobule with hematoxylin and Eosin (H&E) staining demonstrating features of immune checkpoint inhibitor (ICI)-induced hepatitis with moderate lobular hepatitis, scattered apoptic hepatocytes (A), necro-inflammatory foci with lymphocytosis (B) and portal inflammation with interface activity (C).
Figure 2 Graphical representation of bilirubin (μmol/L) and alanine transferase (ALT [U/L]) trends over a 75-day follow-up period from time of presentation. Prednisolone was commenced on Day 5 post-presentation (*).
curroncol-28-00088-t001_Table 1 Table 1 Comparison of histopathological features of ICI-induced hepatitis, autoimmune hepatitis (AIH) and drug-induced liver injury (DILI). Adapted from Zen et al [2].
Histological Features ICI-Hepatitis AIH DILI
Confluent Necrosis Less common More common More common
Eosinophilic infiltration Uncommon Not specific More common
Bile plugs Uncommon Not specific More common
Plasmacytosis Uncommon Common Not specific
Hepatocellular rosettes Uncommon Common Not specific
Emperipolesis Uncommon Common Not specific
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33617506 | 19,188,841 | 2021-02-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immune-mediated enterocolitis'. | Very Delayed Acute Hepatitis after Pembrolizumab Therapy for Advanced Malignancy: How Long Should We Watch?
Immune checkpoint inhibitors (ICIs) have led to major therapeutic advances in the management of malignancy. Despite promising outcomes for some cancers, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs). These may affect a wide array of organ systems. In particular, ICI-induced hepatitis is diagnostically challenging given its variable natural history and clinical manifestations. The onset of ICI-induced hepatitis often occurs between 6 and 14 weeks after treatment initiation and rarely exhibits delayed presentations or manifests after treatment cessation. We present a case of very delayed-onset ICI-induced hepatitis, stressing the importance of long-term surveillance for immune-indued hepatitis in patients initiated on ICIs even long after treatment cessation.
1. Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the prognosis of patients with some cancers. These novel agents augment the immune system by downregulating inhibitors of the anti-cancer immune response, including: cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), program cell death receptor 1 (PD-1) and its ligand—programmed cell death ligand 1 (PD-L1) [1]. Despite promising clinical outcomes, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs) due to the induction of autoimmunity. IrAEs have the potential to affect a wide range of organ systems, commonly including: dermatological (skin rashes), endocrine, gastrointestinal and hepatic. As ICI therapy becomes more widespread in cancer management, IrAEs are becoming more common, including immune-induced hepatitis. We present a case of very delayed-onset ICI-induced hepatitis that occurred 7 months post-treatment cessation, thereby highlighting the importance of prolonged monitoring for an acute hepatitis with careful consideration of its diagnostic and treatment nuances.
2. Case Report
Written informed consent has been obtained from the patient to publish this paper.
A 78-year-old female with stage IIIC breast cancer presented with subacute onset of jaundice. Her breast cancer had been treated with pembrolizumab for 5 months and ceased 7 months prior to presentation. She developed a prodrome of progressive fatigue and anorexia over 2 weeks. There were no recent medication changes other than oral mesalazine, which was commenced 3 months prior due to a new diagnosis of unspecified left-sided colitis confirmed during colonoscopy (possibly immune mediated).
She was diagnosed with stage IIIB triple negative inflammatory breast cancer in 2015. This was treated with neoadjuvant chemotherapy and surgery with subsequent adjuvant radiotherapy. Approximately 12 months prior to her presentation, she developed a locally advanced right breast recurrence requiring neoadjuvant chemotherapy and PD-1 inhibitor (pembrolizumab) prior to double mastectomy.
Initial biochemistry revealed a severe transaminitis. Her bilirubin was 199 μmol/L (<20 μmol/L) with an alanine transferase (ALT) of 1519 U/L (<40 U/L), gamma-glutamyltransferase (GGT) of 440 U/L (<60U/L) and alkaline phosphatase (ALP) of 208 (<130 U/L). She had preserved synthetic function with an international normalised ratio (INR) of 1.0 (<1.2) and an albumin of 31 g/L (34–54 g/L). Her viral hepatitis serology including hepatitis E virus, cytomegalovirus and Epstein–Barr virus was negative. A liver autoantibody screen was non-contributory. Her immunoglobulin G (IgG) titre was 9.4g/L (7–16 g/L). A liver ultrasound and subsequent magnetic resonance cholangiopancreatography (MRCP) showed no structural abnormalities or metastatic disease.
The patient was admitted for 2 weeks with a provisional diagnosis of drug-induced liver injury (DILI) secondary to mesalazine or immunotherapy. Mesalazine was ceased and she was managed expectantly. On Day 5, her liver function tests (LFTs) worsened, her bilirubin peaked at 205 μmol/L with an ALT of 1543 U/L. A liver biopsy revealed pan-lobular hepatitis with scattered apoptic hepatocytes, necro-inflammatory foci, lymphocytosis and foci of interface activity consistent with ICI-induced hepatitis (Figure 1). Given the biopsy results, she was initiated on 50 mg of oral prednisolone (1 mg/kg/day) to minimise glucocorticoid-related side effects. The patient’s clinical and biochemical status improved with a daily downtrend in LFTs, and resolution of her fatigue and anorexia (Figure 2). She was subsequently discharged with regular LFT monitoring and a slow glucocorticoid taper.
Considering her biopsy results and rapid resolution of liver function whilst on glucocorticoid therapy, a diagnosis of delayed immune-induced hepatitis secondary to pembrolizumab was made.
3. Discussion
The clinical manifestations and natural history of ICI-induced hepatitis are heterogenous. Acute hepatitis occurs in 2–10% of patients on ICI therapy, which typically presents as an asymptomatic transaminitis [2,3]. Occasionally, patients may develop a rapidly progressive acute hepatitis and even fulminant liver failure associated with significant morbidity and mortality [4,5]. Contrary to the usual timeframe for disease onset, our patient developed ICI-induced hepatitis 7 months post-treatment cessation. Only one other author has reported a case of delayed ICI-induced hepatitis occurring 8 months post-nivolumab cessation [6]. Delayed-onset immune-induced hepatitis after treatment cessation is rare and most reported cases occur during active treatment—between 6 and 14 weeks after treatment initiation [7]. Hence, this case serves as a reminder to strictly monitor liver function monitoring up to 12 months post-treatment cessation to detect an evolving hepatitis.
ICI-induced hepatitis can be pathologically difficult to differentiate from autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). Contrasting with AIH, auto-antibodies including anti-nuclear and anti-smooth muscle antibodies may be negative in ICI-induced hepatitis. Similarly, serum IgG levels are normal or slightly elevated in ICI-induced hepatitis as exemplified by our case [2]. Liver biopsy is often not required in suspected ICI-induced hepatitis and is only indicated to exclude other causes of acute hepatitis or quantify the degree of hepatocellular injury. Biopsy findings in ICI-induced hepatitis are variable. Most commonly, panlobular hepatitis is observed in approximately 70% of cases, typified by scattered focal necrosis and acidophilic bodies [8]. Histopathological factors which differentiate AIH and DILI from ICP-hepatitis are summarised in Table 1 [2]. In our case, liver biopsy demonstrated classical features of ICI-induced hepatitis without features of AIH or DILI from mesalazine. The cellular infiltrate was suggestive of ICI-related pathology given a lymphocytic predominance without plasmacytosis nor eosinophilia. Detailed knowledge around the pathological and biochemical intricacies of ICI-induced hepatitis can greatly assist with prompt diagnosis and treatment.
Management of ICI-induced hepatitis is based on the Common Terminology Criteria for Adverse Events (CTCAE), which grades severity of disease from 1–4 [3]. Our patient presented with grade 4 hepatitis which was glucocorticoid responsive. Current guidelines advocate for prompt glucocorticoid treatment with methylprednisolone or equivalent at 1–2 mg/kg/day for three days (up to 1 g/day), followed by prednisolone 1–2 mg/kg/day over 4 weeks. In steroid-refractory cases, the introduction of mycophenolate or azathioprine is prudent. Permanent discontinuation of ICI therapy is recommended in grade 3–4 hepatitis [3,9]. Corticosteroid therapy in ICI-induced hepatitis is contentious. Spontaneous improvement in LFTs can occur with observation and low doses of corticosteroids may be sufficient to control disease [5]. Our patient was promptly commenced on prednisolone therapy at a relatively low starting dose compared with pulsed methylprednisolone with rapid clinical response and excellent efficacy. Our case supports that LFT resolution is achievable with a lower dose glucocorticoid, thereby reducing glucocorticoid-related side effects. Further high-quality randomised-controlled studies are required to assess optimal management strategies for ICI-induced hepatitis.
Delayed-onset IrAEs of any organ system are underrecognised and clinical vigilance is critical even after treatment cessation [10]. The median interval to delayed-onset IrAE diagnosis is 6 months post-immunotherapy cessation (IQR 3–28 months) [10]. Currently, there is a paucity of evidence on delayed-onset IrAEs due to limited follow up periods and incompleteness of IrAE reporting in immuno-oncology clinical trials [11]. Best practice guidelines allude to monitoring for delayed-onset IrAEs up to 12 months after treatment discontinuation [9]. However, late-onset IrAEs are difficult to predict with available investigations and are challenging to prevent. Surveillance for IrAEs should be individualised based on a patient’s risk profile for developing IrAEs. A patient’s risk for IrAEs is increased in the presence of patient and treatment factors including: pre-existing connective tissue, vasculitic or auto-immune disease, and combination ICI usage [1]. The utility of active surveillance strategies for delayed-onset IrAEs remains an area of active research with no evidence-based algorithms available.
4. Conclusions
ICIs are becoming an integral part of cancer therapy, and monitoring for adverse events requires awareness from all physicians and not just oncologists. This case pertinently emphasises the importance of long-term surveillance for immune-induced hepatitis in patients initiated on ICI therapy. Attentive appraisal of symptoms, signs and investigations is required for prompt diagnosis of ICI-induced hepatitis allowing for the timely introduction of therapy. Systemic treatment is nuanced and further high-quality evidence is required to guide optimal therapy. We advocate for individualised surveillance strategies for delayed-onset IrAEs up to 12-months after treatment cessation. However, stringent evidence-based surveillance protocols remains an area of ongoing development.
5. Clinical Practice Points
Delayed-onset ICI-induced hepatitis can occur up to 12 months post-treatment cessation;
Autoimmune biomarkers are often negative in ICI-induced hepatitis and plasmacytosis or eosinophilia is uncommon in the biopsy cellular infiltrate;
Low-dose glucocorticoid therapy may be warranted in select ICI-induced hepatitis patients, but further randomized control studies are required to assess optimal glucocorticoid dosing;
Routine monitoring for delayed-onset IrAEs including liver function should be individualised and can extend up to 12 months post-treatment cessation.
Author Contributions
T.P.—case analysis and writing. K.P., L.L., V.K., A.A. and S.P.—review and editing of subsequent drafts. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Histologic examination of liver lobule with hematoxylin and Eosin (H&E) staining demonstrating features of immune checkpoint inhibitor (ICI)-induced hepatitis with moderate lobular hepatitis, scattered apoptic hepatocytes (A), necro-inflammatory foci with lymphocytosis (B) and portal inflammation with interface activity (C).
Figure 2 Graphical representation of bilirubin (μmol/L) and alanine transferase (ALT [U/L]) trends over a 75-day follow-up period from time of presentation. Prednisolone was commenced on Day 5 post-presentation (*).
curroncol-28-00088-t001_Table 1 Table 1 Comparison of histopathological features of ICI-induced hepatitis, autoimmune hepatitis (AIH) and drug-induced liver injury (DILI). Adapted from Zen et al [2].
Histological Features ICI-Hepatitis AIH DILI
Confluent Necrosis Less common More common More common
Eosinophilic infiltration Uncommon Not specific More common
Bile plugs Uncommon Not specific More common
Plasmacytosis Uncommon Common Not specific
Hepatocellular rosettes Uncommon Common Not specific
Emperipolesis Uncommon Common Not specific
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33617506 | 19,188,841 | 2021-02-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immune-mediated hepatitis'. | Very Delayed Acute Hepatitis after Pembrolizumab Therapy for Advanced Malignancy: How Long Should We Watch?
Immune checkpoint inhibitors (ICIs) have led to major therapeutic advances in the management of malignancy. Despite promising outcomes for some cancers, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs). These may affect a wide array of organ systems. In particular, ICI-induced hepatitis is diagnostically challenging given its variable natural history and clinical manifestations. The onset of ICI-induced hepatitis often occurs between 6 and 14 weeks after treatment initiation and rarely exhibits delayed presentations or manifests after treatment cessation. We present a case of very delayed-onset ICI-induced hepatitis, stressing the importance of long-term surveillance for immune-indued hepatitis in patients initiated on ICIs even long after treatment cessation.
1. Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the prognosis of patients with some cancers. These novel agents augment the immune system by downregulating inhibitors of the anti-cancer immune response, including: cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), program cell death receptor 1 (PD-1) and its ligand—programmed cell death ligand 1 (PD-L1) [1]. Despite promising clinical outcomes, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs) due to the induction of autoimmunity. IrAEs have the potential to affect a wide range of organ systems, commonly including: dermatological (skin rashes), endocrine, gastrointestinal and hepatic. As ICI therapy becomes more widespread in cancer management, IrAEs are becoming more common, including immune-induced hepatitis. We present a case of very delayed-onset ICI-induced hepatitis that occurred 7 months post-treatment cessation, thereby highlighting the importance of prolonged monitoring for an acute hepatitis with careful consideration of its diagnostic and treatment nuances.
2. Case Report
Written informed consent has been obtained from the patient to publish this paper.
A 78-year-old female with stage IIIC breast cancer presented with subacute onset of jaundice. Her breast cancer had been treated with pembrolizumab for 5 months and ceased 7 months prior to presentation. She developed a prodrome of progressive fatigue and anorexia over 2 weeks. There were no recent medication changes other than oral mesalazine, which was commenced 3 months prior due to a new diagnosis of unspecified left-sided colitis confirmed during colonoscopy (possibly immune mediated).
She was diagnosed with stage IIIB triple negative inflammatory breast cancer in 2015. This was treated with neoadjuvant chemotherapy and surgery with subsequent adjuvant radiotherapy. Approximately 12 months prior to her presentation, she developed a locally advanced right breast recurrence requiring neoadjuvant chemotherapy and PD-1 inhibitor (pembrolizumab) prior to double mastectomy.
Initial biochemistry revealed a severe transaminitis. Her bilirubin was 199 μmol/L (<20 μmol/L) with an alanine transferase (ALT) of 1519 U/L (<40 U/L), gamma-glutamyltransferase (GGT) of 440 U/L (<60U/L) and alkaline phosphatase (ALP) of 208 (<130 U/L). She had preserved synthetic function with an international normalised ratio (INR) of 1.0 (<1.2) and an albumin of 31 g/L (34–54 g/L). Her viral hepatitis serology including hepatitis E virus, cytomegalovirus and Epstein–Barr virus was negative. A liver autoantibody screen was non-contributory. Her immunoglobulin G (IgG) titre was 9.4g/L (7–16 g/L). A liver ultrasound and subsequent magnetic resonance cholangiopancreatography (MRCP) showed no structural abnormalities or metastatic disease.
The patient was admitted for 2 weeks with a provisional diagnosis of drug-induced liver injury (DILI) secondary to mesalazine or immunotherapy. Mesalazine was ceased and she was managed expectantly. On Day 5, her liver function tests (LFTs) worsened, her bilirubin peaked at 205 μmol/L with an ALT of 1543 U/L. A liver biopsy revealed pan-lobular hepatitis with scattered apoptic hepatocytes, necro-inflammatory foci, lymphocytosis and foci of interface activity consistent with ICI-induced hepatitis (Figure 1). Given the biopsy results, she was initiated on 50 mg of oral prednisolone (1 mg/kg/day) to minimise glucocorticoid-related side effects. The patient’s clinical and biochemical status improved with a daily downtrend in LFTs, and resolution of her fatigue and anorexia (Figure 2). She was subsequently discharged with regular LFT monitoring and a slow glucocorticoid taper.
Considering her biopsy results and rapid resolution of liver function whilst on glucocorticoid therapy, a diagnosis of delayed immune-induced hepatitis secondary to pembrolizumab was made.
3. Discussion
The clinical manifestations and natural history of ICI-induced hepatitis are heterogenous. Acute hepatitis occurs in 2–10% of patients on ICI therapy, which typically presents as an asymptomatic transaminitis [2,3]. Occasionally, patients may develop a rapidly progressive acute hepatitis and even fulminant liver failure associated with significant morbidity and mortality [4,5]. Contrary to the usual timeframe for disease onset, our patient developed ICI-induced hepatitis 7 months post-treatment cessation. Only one other author has reported a case of delayed ICI-induced hepatitis occurring 8 months post-nivolumab cessation [6]. Delayed-onset immune-induced hepatitis after treatment cessation is rare and most reported cases occur during active treatment—between 6 and 14 weeks after treatment initiation [7]. Hence, this case serves as a reminder to strictly monitor liver function monitoring up to 12 months post-treatment cessation to detect an evolving hepatitis.
ICI-induced hepatitis can be pathologically difficult to differentiate from autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). Contrasting with AIH, auto-antibodies including anti-nuclear and anti-smooth muscle antibodies may be negative in ICI-induced hepatitis. Similarly, serum IgG levels are normal or slightly elevated in ICI-induced hepatitis as exemplified by our case [2]. Liver biopsy is often not required in suspected ICI-induced hepatitis and is only indicated to exclude other causes of acute hepatitis or quantify the degree of hepatocellular injury. Biopsy findings in ICI-induced hepatitis are variable. Most commonly, panlobular hepatitis is observed in approximately 70% of cases, typified by scattered focal necrosis and acidophilic bodies [8]. Histopathological factors which differentiate AIH and DILI from ICP-hepatitis are summarised in Table 1 [2]. In our case, liver biopsy demonstrated classical features of ICI-induced hepatitis without features of AIH or DILI from mesalazine. The cellular infiltrate was suggestive of ICI-related pathology given a lymphocytic predominance without plasmacytosis nor eosinophilia. Detailed knowledge around the pathological and biochemical intricacies of ICI-induced hepatitis can greatly assist with prompt diagnosis and treatment.
Management of ICI-induced hepatitis is based on the Common Terminology Criteria for Adverse Events (CTCAE), which grades severity of disease from 1–4 [3]. Our patient presented with grade 4 hepatitis which was glucocorticoid responsive. Current guidelines advocate for prompt glucocorticoid treatment with methylprednisolone or equivalent at 1–2 mg/kg/day for three days (up to 1 g/day), followed by prednisolone 1–2 mg/kg/day over 4 weeks. In steroid-refractory cases, the introduction of mycophenolate or azathioprine is prudent. Permanent discontinuation of ICI therapy is recommended in grade 3–4 hepatitis [3,9]. Corticosteroid therapy in ICI-induced hepatitis is contentious. Spontaneous improvement in LFTs can occur with observation and low doses of corticosteroids may be sufficient to control disease [5]. Our patient was promptly commenced on prednisolone therapy at a relatively low starting dose compared with pulsed methylprednisolone with rapid clinical response and excellent efficacy. Our case supports that LFT resolution is achievable with a lower dose glucocorticoid, thereby reducing glucocorticoid-related side effects. Further high-quality randomised-controlled studies are required to assess optimal management strategies for ICI-induced hepatitis.
Delayed-onset IrAEs of any organ system are underrecognised and clinical vigilance is critical even after treatment cessation [10]. The median interval to delayed-onset IrAE diagnosis is 6 months post-immunotherapy cessation (IQR 3–28 months) [10]. Currently, there is a paucity of evidence on delayed-onset IrAEs due to limited follow up periods and incompleteness of IrAE reporting in immuno-oncology clinical trials [11]. Best practice guidelines allude to monitoring for delayed-onset IrAEs up to 12 months after treatment discontinuation [9]. However, late-onset IrAEs are difficult to predict with available investigations and are challenging to prevent. Surveillance for IrAEs should be individualised based on a patient’s risk profile for developing IrAEs. A patient’s risk for IrAEs is increased in the presence of patient and treatment factors including: pre-existing connective tissue, vasculitic or auto-immune disease, and combination ICI usage [1]. The utility of active surveillance strategies for delayed-onset IrAEs remains an area of active research with no evidence-based algorithms available.
4. Conclusions
ICIs are becoming an integral part of cancer therapy, and monitoring for adverse events requires awareness from all physicians and not just oncologists. This case pertinently emphasises the importance of long-term surveillance for immune-induced hepatitis in patients initiated on ICI therapy. Attentive appraisal of symptoms, signs and investigations is required for prompt diagnosis of ICI-induced hepatitis allowing for the timely introduction of therapy. Systemic treatment is nuanced and further high-quality evidence is required to guide optimal therapy. We advocate for individualised surveillance strategies for delayed-onset IrAEs up to 12-months after treatment cessation. However, stringent evidence-based surveillance protocols remains an area of ongoing development.
5. Clinical Practice Points
Delayed-onset ICI-induced hepatitis can occur up to 12 months post-treatment cessation;
Autoimmune biomarkers are often negative in ICI-induced hepatitis and plasmacytosis or eosinophilia is uncommon in the biopsy cellular infiltrate;
Low-dose glucocorticoid therapy may be warranted in select ICI-induced hepatitis patients, but further randomized control studies are required to assess optimal glucocorticoid dosing;
Routine monitoring for delayed-onset IrAEs including liver function should be individualised and can extend up to 12 months post-treatment cessation.
Author Contributions
T.P.—case analysis and writing. K.P., L.L., V.K., A.A. and S.P.—review and editing of subsequent drafts. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Histologic examination of liver lobule with hematoxylin and Eosin (H&E) staining demonstrating features of immune checkpoint inhibitor (ICI)-induced hepatitis with moderate lobular hepatitis, scattered apoptic hepatocytes (A), necro-inflammatory foci with lymphocytosis (B) and portal inflammation with interface activity (C).
Figure 2 Graphical representation of bilirubin (μmol/L) and alanine transferase (ALT [U/L]) trends over a 75-day follow-up period from time of presentation. Prednisolone was commenced on Day 5 post-presentation (*).
curroncol-28-00088-t001_Table 1 Table 1 Comparison of histopathological features of ICI-induced hepatitis, autoimmune hepatitis (AIH) and drug-induced liver injury (DILI). Adapted from Zen et al [2].
Histological Features ICI-Hepatitis AIH DILI
Confluent Necrosis Less common More common More common
Eosinophilic infiltration Uncommon Not specific More common
Bile plugs Uncommon Not specific More common
Plasmacytosis Uncommon Common Not specific
Hepatocellular rosettes Uncommon Common Not specific
Emperipolesis Uncommon Common Not specific
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33617506 | 19,188,841 | 2021-02-14 |
What was the outcome of reaction 'Death'? | Very Delayed Acute Hepatitis after Pembrolizumab Therapy for Advanced Malignancy: How Long Should We Watch?
Immune checkpoint inhibitors (ICIs) have led to major therapeutic advances in the management of malignancy. Despite promising outcomes for some cancers, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs). These may affect a wide array of organ systems. In particular, ICI-induced hepatitis is diagnostically challenging given its variable natural history and clinical manifestations. The onset of ICI-induced hepatitis often occurs between 6 and 14 weeks after treatment initiation and rarely exhibits delayed presentations or manifests after treatment cessation. We present a case of very delayed-onset ICI-induced hepatitis, stressing the importance of long-term surveillance for immune-indued hepatitis in patients initiated on ICIs even long after treatment cessation.
1. Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the prognosis of patients with some cancers. These novel agents augment the immune system by downregulating inhibitors of the anti-cancer immune response, including: cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), program cell death receptor 1 (PD-1) and its ligand—programmed cell death ligand 1 (PD-L1) [1]. Despite promising clinical outcomes, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs) due to the induction of autoimmunity. IrAEs have the potential to affect a wide range of organ systems, commonly including: dermatological (skin rashes), endocrine, gastrointestinal and hepatic. As ICI therapy becomes more widespread in cancer management, IrAEs are becoming more common, including immune-induced hepatitis. We present a case of very delayed-onset ICI-induced hepatitis that occurred 7 months post-treatment cessation, thereby highlighting the importance of prolonged monitoring for an acute hepatitis with careful consideration of its diagnostic and treatment nuances.
2. Case Report
Written informed consent has been obtained from the patient to publish this paper.
A 78-year-old female with stage IIIC breast cancer presented with subacute onset of jaundice. Her breast cancer had been treated with pembrolizumab for 5 months and ceased 7 months prior to presentation. She developed a prodrome of progressive fatigue and anorexia over 2 weeks. There were no recent medication changes other than oral mesalazine, which was commenced 3 months prior due to a new diagnosis of unspecified left-sided colitis confirmed during colonoscopy (possibly immune mediated).
She was diagnosed with stage IIIB triple negative inflammatory breast cancer in 2015. This was treated with neoadjuvant chemotherapy and surgery with subsequent adjuvant radiotherapy. Approximately 12 months prior to her presentation, she developed a locally advanced right breast recurrence requiring neoadjuvant chemotherapy and PD-1 inhibitor (pembrolizumab) prior to double mastectomy.
Initial biochemistry revealed a severe transaminitis. Her bilirubin was 199 μmol/L (<20 μmol/L) with an alanine transferase (ALT) of 1519 U/L (<40 U/L), gamma-glutamyltransferase (GGT) of 440 U/L (<60U/L) and alkaline phosphatase (ALP) of 208 (<130 U/L). She had preserved synthetic function with an international normalised ratio (INR) of 1.0 (<1.2) and an albumin of 31 g/L (34–54 g/L). Her viral hepatitis serology including hepatitis E virus, cytomegalovirus and Epstein–Barr virus was negative. A liver autoantibody screen was non-contributory. Her immunoglobulin G (IgG) titre was 9.4g/L (7–16 g/L). A liver ultrasound and subsequent magnetic resonance cholangiopancreatography (MRCP) showed no structural abnormalities or metastatic disease.
The patient was admitted for 2 weeks with a provisional diagnosis of drug-induced liver injury (DILI) secondary to mesalazine or immunotherapy. Mesalazine was ceased and she was managed expectantly. On Day 5, her liver function tests (LFTs) worsened, her bilirubin peaked at 205 μmol/L with an ALT of 1543 U/L. A liver biopsy revealed pan-lobular hepatitis with scattered apoptic hepatocytes, necro-inflammatory foci, lymphocytosis and foci of interface activity consistent with ICI-induced hepatitis (Figure 1). Given the biopsy results, she was initiated on 50 mg of oral prednisolone (1 mg/kg/day) to minimise glucocorticoid-related side effects. The patient’s clinical and biochemical status improved with a daily downtrend in LFTs, and resolution of her fatigue and anorexia (Figure 2). She was subsequently discharged with regular LFT monitoring and a slow glucocorticoid taper.
Considering her biopsy results and rapid resolution of liver function whilst on glucocorticoid therapy, a diagnosis of delayed immune-induced hepatitis secondary to pembrolizumab was made.
3. Discussion
The clinical manifestations and natural history of ICI-induced hepatitis are heterogenous. Acute hepatitis occurs in 2–10% of patients on ICI therapy, which typically presents as an asymptomatic transaminitis [2,3]. Occasionally, patients may develop a rapidly progressive acute hepatitis and even fulminant liver failure associated with significant morbidity and mortality [4,5]. Contrary to the usual timeframe for disease onset, our patient developed ICI-induced hepatitis 7 months post-treatment cessation. Only one other author has reported a case of delayed ICI-induced hepatitis occurring 8 months post-nivolumab cessation [6]. Delayed-onset immune-induced hepatitis after treatment cessation is rare and most reported cases occur during active treatment—between 6 and 14 weeks after treatment initiation [7]. Hence, this case serves as a reminder to strictly monitor liver function monitoring up to 12 months post-treatment cessation to detect an evolving hepatitis.
ICI-induced hepatitis can be pathologically difficult to differentiate from autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). Contrasting with AIH, auto-antibodies including anti-nuclear and anti-smooth muscle antibodies may be negative in ICI-induced hepatitis. Similarly, serum IgG levels are normal or slightly elevated in ICI-induced hepatitis as exemplified by our case [2]. Liver biopsy is often not required in suspected ICI-induced hepatitis and is only indicated to exclude other causes of acute hepatitis or quantify the degree of hepatocellular injury. Biopsy findings in ICI-induced hepatitis are variable. Most commonly, panlobular hepatitis is observed in approximately 70% of cases, typified by scattered focal necrosis and acidophilic bodies [8]. Histopathological factors which differentiate AIH and DILI from ICP-hepatitis are summarised in Table 1 [2]. In our case, liver biopsy demonstrated classical features of ICI-induced hepatitis without features of AIH or DILI from mesalazine. The cellular infiltrate was suggestive of ICI-related pathology given a lymphocytic predominance without plasmacytosis nor eosinophilia. Detailed knowledge around the pathological and biochemical intricacies of ICI-induced hepatitis can greatly assist with prompt diagnosis and treatment.
Management of ICI-induced hepatitis is based on the Common Terminology Criteria for Adverse Events (CTCAE), which grades severity of disease from 1–4 [3]. Our patient presented with grade 4 hepatitis which was glucocorticoid responsive. Current guidelines advocate for prompt glucocorticoid treatment with methylprednisolone or equivalent at 1–2 mg/kg/day for three days (up to 1 g/day), followed by prednisolone 1–2 mg/kg/day over 4 weeks. In steroid-refractory cases, the introduction of mycophenolate or azathioprine is prudent. Permanent discontinuation of ICI therapy is recommended in grade 3–4 hepatitis [3,9]. Corticosteroid therapy in ICI-induced hepatitis is contentious. Spontaneous improvement in LFTs can occur with observation and low doses of corticosteroids may be sufficient to control disease [5]. Our patient was promptly commenced on prednisolone therapy at a relatively low starting dose compared with pulsed methylprednisolone with rapid clinical response and excellent efficacy. Our case supports that LFT resolution is achievable with a lower dose glucocorticoid, thereby reducing glucocorticoid-related side effects. Further high-quality randomised-controlled studies are required to assess optimal management strategies for ICI-induced hepatitis.
Delayed-onset IrAEs of any organ system are underrecognised and clinical vigilance is critical even after treatment cessation [10]. The median interval to delayed-onset IrAE diagnosis is 6 months post-immunotherapy cessation (IQR 3–28 months) [10]. Currently, there is a paucity of evidence on delayed-onset IrAEs due to limited follow up periods and incompleteness of IrAE reporting in immuno-oncology clinical trials [11]. Best practice guidelines allude to monitoring for delayed-onset IrAEs up to 12 months after treatment discontinuation [9]. However, late-onset IrAEs are difficult to predict with available investigations and are challenging to prevent. Surveillance for IrAEs should be individualised based on a patient’s risk profile for developing IrAEs. A patient’s risk for IrAEs is increased in the presence of patient and treatment factors including: pre-existing connective tissue, vasculitic or auto-immune disease, and combination ICI usage [1]. The utility of active surveillance strategies for delayed-onset IrAEs remains an area of active research with no evidence-based algorithms available.
4. Conclusions
ICIs are becoming an integral part of cancer therapy, and monitoring for adverse events requires awareness from all physicians and not just oncologists. This case pertinently emphasises the importance of long-term surveillance for immune-induced hepatitis in patients initiated on ICI therapy. Attentive appraisal of symptoms, signs and investigations is required for prompt diagnosis of ICI-induced hepatitis allowing for the timely introduction of therapy. Systemic treatment is nuanced and further high-quality evidence is required to guide optimal therapy. We advocate for individualised surveillance strategies for delayed-onset IrAEs up to 12-months after treatment cessation. However, stringent evidence-based surveillance protocols remains an area of ongoing development.
5. Clinical Practice Points
Delayed-onset ICI-induced hepatitis can occur up to 12 months post-treatment cessation;
Autoimmune biomarkers are often negative in ICI-induced hepatitis and plasmacytosis or eosinophilia is uncommon in the biopsy cellular infiltrate;
Low-dose glucocorticoid therapy may be warranted in select ICI-induced hepatitis patients, but further randomized control studies are required to assess optimal glucocorticoid dosing;
Routine monitoring for delayed-onset IrAEs including liver function should be individualised and can extend up to 12 months post-treatment cessation.
Author Contributions
T.P.—case analysis and writing. K.P., L.L., V.K., A.A. and S.P.—review and editing of subsequent drafts. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Histologic examination of liver lobule with hematoxylin and Eosin (H&E) staining demonstrating features of immune checkpoint inhibitor (ICI)-induced hepatitis with moderate lobular hepatitis, scattered apoptic hepatocytes (A), necro-inflammatory foci with lymphocytosis (B) and portal inflammation with interface activity (C).
Figure 2 Graphical representation of bilirubin (μmol/L) and alanine transferase (ALT [U/L]) trends over a 75-day follow-up period from time of presentation. Prednisolone was commenced on Day 5 post-presentation (*).
curroncol-28-00088-t001_Table 1 Table 1 Comparison of histopathological features of ICI-induced hepatitis, autoimmune hepatitis (AIH) and drug-induced liver injury (DILI). Adapted from Zen et al [2].
Histological Features ICI-Hepatitis AIH DILI
Confluent Necrosis Less common More common More common
Eosinophilic infiltration Uncommon Not specific More common
Bile plugs Uncommon Not specific More common
Plasmacytosis Uncommon Common Not specific
Hepatocellular rosettes Uncommon Common Not specific
Emperipolesis Uncommon Common Not specific
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 33617506 | 19,188,841 | 2021-02-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Not COVID-19, Don't Overlook Pneumocystis in Patients on Gefitinib!
An 82-year-old woman treated for advanced lung cancer with gefitinb was admitted to the emergency unit complaining of dyspnea. Chest computed tomography found abnormalities classified as possible diffuse COVID-19 pneumonia. RT-PCR for Sars-Cov-2 was twice negative. PCR for Pneumocystis jirovecii was positive on bronchoalveolar lavage. The final diagnosis was Pneumocystis jirovecii pneumonia. Therefore, physicians must be careful not to misdiagnose COVID-19, especially in cancer patients on small-molecule therapeutics like gefitinib and corticosteroids.
1. Introduction
Since December 2019, the medical community has been dealing with the SARS-CoV-2 pandemic. We report here an original case where the focus on an erroneous diagnosis of COVID-19 delayed the management of a Pneumocystis jirovecii infection acquired during treatment with gefitinb, a tyrosine kinase inhibitor (TKI), for lung cancer.
2. Case Presentation
An 82-year-old woman complaining of dyspnea was admitted to the emergency unit of a French university hospital in October 2020, during the SARS-CoV-2 pandemic. She had been diagnosed with locally advanced lung adenocarcinoma (T2N2M0 with EGFR L858R activating mutation) in June 2020. The patient refused any surgical or radiotherapy treatment. Osimertinib was prescribed as a first-line treatment, but after one month, the woman developed pneumonitis whose origin, after multidisciplinary consultation, was possibly attributed to osimertinib. Corticosteroid therapy with betamethasone was initiated at 6 mg and then rapidly tapered, resulting in good resolution of the pneumonitis. After six weeks, when betamethasone had been reduced to a dose of 1 mg, corticosteroid therapy was switched to hydrocortisone 20 mg. Osimertinib was replaced by gefitinib after two weeks of corticosteroid therapy. No antifungal prophylaxis was initiated. After the switch to gefitinb and low-dose hydrocortisone, tolerance was found to be excellent, and the control PET (positron emission tomography) scan performed at the end of September 2020 showed a complete metabolic response and the absence of pneumonitis.
The woman’s current complaint started a couple of days before with dyspnea, delirium, and fever. Diffuse rhonchi were found on pulmonary auscultation. The results of the blood analysis were as follows: leukocytes 8.1 × 109 cells/L, neutrophils 7 × 109 cells/L, lymphocytes 0.46 × 109 cells/L, platelets 398 × 109 cells/L, hemoglobin 10.1 g/dL, and C-reactive protein 341 mg/L. The chest computed tomography (CT) scan showed multiple bilateral apical and peri-hilar ground glass opacities (GGO) associated with subpleural condensation. These findings were classified as possible diffuse COVID-19 pneumonia (Figure 1) by the radiologist [1]. However, the RT-PCR (Reverse Transcription Polymerase Chain Reaction) for SARS-CoV-2 performed on nasopharyngeal swab on admission, two days after the symptoms began, was negative. A diagnosis of COVID-19 was nonetheless initially retained and the patient received dexamethasone recommended by the Recovery trial [2,3]. When the initial course was not favorable, oxygen therapy was increased, and a second RT-PCR for Sars-Cov-2 was negative. We performed a blood (1-3)-Beta-D-glucan test, which was positive at 90 pg/mL (negative <60 pg/mL, equivocal between 60 and 80 pg/mL, positive above 80 pg/mL). PCR for Pneumocystis jirovecii was positive on bronchoalveolar lavage. The final diagnosis was Pneumocystis jirovecii pneumonia (PJP), and the patient responded favorably to treatment with sulfamethoxazole-trimethoprim (SMX-TMP). After discussion with the pulmonologists, gefitinib was considered to be potentially responsible for the infection.
3. Discussion
In this case, the physicians initially focused on the findings of the chest CT. In COVID-19, the typical features of CT imaging are bilateral, multifocal rounded, and peripheral GGO, with or without consolidations or visible intralobular lines, also known as “crazy paving” [4]. GGO is a common CT sign in interstitial lung disease [5]. There are numerous etiologies, and Pneumocystis is a well-known cause of CT abnormalities in immunocompromised patients [6,7]. PJP has been reported in some non-small-cell lung cancer patients treated with radiochemotherapy or prolonged corticosteroid therapy [8,9]. PJP mainly occurs in patients with defective CD4 T-lymphocyte–macrophage crosstalk [10]. Our patient was obviously immunocompromised with profound lymphopenia, which could be explained by both the cancer and immunosenescence [11]. Here, the role of corticosteroid therapy at the beginning of the infection cannot be excluded, especially since the patient was not taking SMX-TMP prophylaxis. However, the rapid decrease and the very low dose of hydrocortisone taken for several weeks led to the hypothesis of the imputability of the TKI. Several TKIs such as idelalisib are known to generate a higher risk of PJP [7,12]. Most invasive fungal infections described in the literature involve TKIs inhibiting the PI3K pathway, while gefitinib inhibits the Ras signaling pathway by inhibiting EGFR autophosphorylation [13,14]. While gefitinib has not been associated with more frequent infections, particular attention should be paid to such events in patients treated with TKIs [10]. At least, previous prolonged administration of corticosteroids may have contributed to the development of PJP. Nonetheless, this is the first case of PJP diagnosed in a patient treated with gefitinib.
4. Conclusions
Physicians must be careful not to misdiagnose COVID-19, especially in cancer patients on small-molecule therapeutics. Prolonged corticosteroids and TKI anti-EGFR like gefitinib could increase the risk of PJP. SMX-TMP prophylaxis could be routinely discussed for patients on TKIs, especially those with corticosteroid intake.
Acknowledgments
The authors are grateful to Suzanne RANKIN, a native English speaker, who read and corrected this article.
Author Contributions
Conceptualization, J.B. and V.Q.; methodology, J.B.; validation, A.P. and P.M.; investigation, J.B.; data curation, J.V.; writing—original draft preparation J.B.; writing—review and editing, J.B.; visualization, J.B.; supervision, P.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Chest computed tomography (CT) of an 82-year-old woman with advanced lung adenocarcinoma successfully treated with gefitinib and admitted for dyspnea two days previously. Bilateral ground glass opacities (*), and subpleural condensation (→) were interpreted as possible diffuse COVID-19 pneumonia. Note the absence of crazy paving aspect. RT-PCR on nasopharyngeal swab was negative for Sars-Cov-2 twice. A final diagnosis of Pneumocystis jirovecii pneumonia on gefitinib (a tyrosine kinase inhibitor) was retained after positive blood (1-3)-Beta-D-glucane and PCR for P. jirovecii on bronchoalveolar lavage.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BETAMETHASONE, GEFITINIB, HYDROCORTISONE, OSIMERTINIB | DrugsGivenReaction | CC BY | 33617512 | 19,083,915 | 2021-02-21 |
What was the outcome of reaction 'Pneumocystis jirovecii pneumonia'? | Not COVID-19, Don't Overlook Pneumocystis in Patients on Gefitinib!
An 82-year-old woman treated for advanced lung cancer with gefitinb was admitted to the emergency unit complaining of dyspnea. Chest computed tomography found abnormalities classified as possible diffuse COVID-19 pneumonia. RT-PCR for Sars-Cov-2 was twice negative. PCR for Pneumocystis jirovecii was positive on bronchoalveolar lavage. The final diagnosis was Pneumocystis jirovecii pneumonia. Therefore, physicians must be careful not to misdiagnose COVID-19, especially in cancer patients on small-molecule therapeutics like gefitinib and corticosteroids.
1. Introduction
Since December 2019, the medical community has been dealing with the SARS-CoV-2 pandemic. We report here an original case where the focus on an erroneous diagnosis of COVID-19 delayed the management of a Pneumocystis jirovecii infection acquired during treatment with gefitinb, a tyrosine kinase inhibitor (TKI), for lung cancer.
2. Case Presentation
An 82-year-old woman complaining of dyspnea was admitted to the emergency unit of a French university hospital in October 2020, during the SARS-CoV-2 pandemic. She had been diagnosed with locally advanced lung adenocarcinoma (T2N2M0 with EGFR L858R activating mutation) in June 2020. The patient refused any surgical or radiotherapy treatment. Osimertinib was prescribed as a first-line treatment, but after one month, the woman developed pneumonitis whose origin, after multidisciplinary consultation, was possibly attributed to osimertinib. Corticosteroid therapy with betamethasone was initiated at 6 mg and then rapidly tapered, resulting in good resolution of the pneumonitis. After six weeks, when betamethasone had been reduced to a dose of 1 mg, corticosteroid therapy was switched to hydrocortisone 20 mg. Osimertinib was replaced by gefitinib after two weeks of corticosteroid therapy. No antifungal prophylaxis was initiated. After the switch to gefitinb and low-dose hydrocortisone, tolerance was found to be excellent, and the control PET (positron emission tomography) scan performed at the end of September 2020 showed a complete metabolic response and the absence of pneumonitis.
The woman’s current complaint started a couple of days before with dyspnea, delirium, and fever. Diffuse rhonchi were found on pulmonary auscultation. The results of the blood analysis were as follows: leukocytes 8.1 × 109 cells/L, neutrophils 7 × 109 cells/L, lymphocytes 0.46 × 109 cells/L, platelets 398 × 109 cells/L, hemoglobin 10.1 g/dL, and C-reactive protein 341 mg/L. The chest computed tomography (CT) scan showed multiple bilateral apical and peri-hilar ground glass opacities (GGO) associated with subpleural condensation. These findings were classified as possible diffuse COVID-19 pneumonia (Figure 1) by the radiologist [1]. However, the RT-PCR (Reverse Transcription Polymerase Chain Reaction) for SARS-CoV-2 performed on nasopharyngeal swab on admission, two days after the symptoms began, was negative. A diagnosis of COVID-19 was nonetheless initially retained and the patient received dexamethasone recommended by the Recovery trial [2,3]. When the initial course was not favorable, oxygen therapy was increased, and a second RT-PCR for Sars-Cov-2 was negative. We performed a blood (1-3)-Beta-D-glucan test, which was positive at 90 pg/mL (negative <60 pg/mL, equivocal between 60 and 80 pg/mL, positive above 80 pg/mL). PCR for Pneumocystis jirovecii was positive on bronchoalveolar lavage. The final diagnosis was Pneumocystis jirovecii pneumonia (PJP), and the patient responded favorably to treatment with sulfamethoxazole-trimethoprim (SMX-TMP). After discussion with the pulmonologists, gefitinib was considered to be potentially responsible for the infection.
3. Discussion
In this case, the physicians initially focused on the findings of the chest CT. In COVID-19, the typical features of CT imaging are bilateral, multifocal rounded, and peripheral GGO, with or without consolidations or visible intralobular lines, also known as “crazy paving” [4]. GGO is a common CT sign in interstitial lung disease [5]. There are numerous etiologies, and Pneumocystis is a well-known cause of CT abnormalities in immunocompromised patients [6,7]. PJP has been reported in some non-small-cell lung cancer patients treated with radiochemotherapy or prolonged corticosteroid therapy [8,9]. PJP mainly occurs in patients with defective CD4 T-lymphocyte–macrophage crosstalk [10]. Our patient was obviously immunocompromised with profound lymphopenia, which could be explained by both the cancer and immunosenescence [11]. Here, the role of corticosteroid therapy at the beginning of the infection cannot be excluded, especially since the patient was not taking SMX-TMP prophylaxis. However, the rapid decrease and the very low dose of hydrocortisone taken for several weeks led to the hypothesis of the imputability of the TKI. Several TKIs such as idelalisib are known to generate a higher risk of PJP [7,12]. Most invasive fungal infections described in the literature involve TKIs inhibiting the PI3K pathway, while gefitinib inhibits the Ras signaling pathway by inhibiting EGFR autophosphorylation [13,14]. While gefitinib has not been associated with more frequent infections, particular attention should be paid to such events in patients treated with TKIs [10]. At least, previous prolonged administration of corticosteroids may have contributed to the development of PJP. Nonetheless, this is the first case of PJP diagnosed in a patient treated with gefitinib.
4. Conclusions
Physicians must be careful not to misdiagnose COVID-19, especially in cancer patients on small-molecule therapeutics. Prolonged corticosteroids and TKI anti-EGFR like gefitinib could increase the risk of PJP. SMX-TMP prophylaxis could be routinely discussed for patients on TKIs, especially those with corticosteroid intake.
Acknowledgments
The authors are grateful to Suzanne RANKIN, a native English speaker, who read and corrected this article.
Author Contributions
Conceptualization, J.B. and V.Q.; methodology, J.B.; validation, A.P. and P.M.; investigation, J.B.; data curation, J.V.; writing—original draft preparation J.B.; writing—review and editing, J.B.; visualization, J.B.; supervision, P.M. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Chest computed tomography (CT) of an 82-year-old woman with advanced lung adenocarcinoma successfully treated with gefitinib and admitted for dyspnea two days previously. Bilateral ground glass opacities (*), and subpleural condensation (→) were interpreted as possible diffuse COVID-19 pneumonia. Note the absence of crazy paving aspect. RT-PCR on nasopharyngeal swab was negative for Sars-Cov-2 twice. A final diagnosis of Pneumocystis jirovecii pneumonia on gefitinib (a tyrosine kinase inhibitor) was retained after positive blood (1-3)-Beta-D-glucane and PCR for P. jirovecii on bronchoalveolar lavage.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33617512 | 19,064,604 | 2021-02-21 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug abuse'. | Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.
BACKGROUND
The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare.
METHODS
Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid.
CONCLUSIONS
This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Background
The mu-opioid agonist methadone is administered orally and is widely used in opioid detoxification and maintenance programs and in the treatment of moderate-to-severe pain in some countries. Oral methadone–use and –abuse have been associated with potential inflammatory and toxic central nervous system (CNS) adverse effects such as cerebellitis [1] and delayed-onset toxic leukoencephalopathy [2–4]. Moreover, cognitive deficits have been reported in long-term methadone users [5]. However, case reports of intravenous methadone application [6] are rare and limited to ischemic changes or hypoxia-induced encephalopathy.
Here, we report a 19-year old male patient who subsequently to recreational intravenous methadone-abuse initially presented with acute neurological deficits with magnetic resonance imaging changes in the bilateral basal ganglia and the cerebellum. Subsequently, the patient developed wide-spread white matter T2-hyperintense lesions and delayed-onset encephalopathy accompanied by signs of secondary inflammation. Cerebral spinal fluid (CSF) flow cytometry revealed an inversion of monocyte and natural killer cell subsets while extensive neuropsychological examination demonstrated persistent cognitive deficits. This suggests a potential sequential toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Case presentation
A 19-year old Caucasian male presented to the University Hospital of Muenster emergency department after being unresponsive for 5 h. After consuming liquid methadone intravenously the night before, the patient awoke and immediately complained of partial bilateral hearing loss, walking impairment and numbness of both inner thighs.
According to third-party history obtained from two accompanying friends (the patient was amnestic regarding the night before) the patient had consumed 3 × 2.5 mL of liquid methadone (produced for substitution therapy) intravenously. They reported observing unconsciousness, urinary incontinence, and a twist of his eyes. The patient and accompanying friends admitted to occasionally orally using illegally obtained methadone and cannabis but credibly denied consuming these substances or other opiods and illegal drugs in the days before. This was the first event of intravenous methadone abuse. The medical history of the patient was otherwise unremarkable.
In the neurological examination the patient presented fluctuating consciousness, severe psychomotor and cognitive slowing (slowed speech, increased response latency, concentration deficits), mild paraparesis of the lower limbs, clonus when testing the left patellar reflex and symmetrical bilateral hypoesthesia of the inner thigh. Medical examination showed a heart rate of 76 beats per minute, blood pressure 121/73 mmHg, peripheral oxygen saturation of 97% and temperature of 36.8 °C. An electrocardiogram (ECG) showed only unspecific change of the ST-segment in V2 and V3. FAST-ultrasound did not reveal any abnormalities.
Blood tests revealed a slightly elevated c-reactive protein (5.2 mg/dl; reference < .5 mg/dl), an elevated GOP (400 U /l; reference: < 30 U/l), GPT (118 U/l; reference < 40 U /l) and an increased creatin-kinase (7104 U/l; reference: < 174 U/l) and lactatdehydrogenase (563 U/l; reference 117–217 U/l). Sodium and potassium levels were within normal range. Intoxication screening of the urine was positive for methadone (2.55 mg/l) and cannabinoids (THC-COOH: 29 μg/l) but was negative for other drugs including non-methadone opioids and barbiturates, benzodiazepines, tricyclic antidepressive drugs, methamphetamines, cocaine, phencyclidine and paracetamol. An initial magnetic resonance imaging (MRI) showed multifocal, bilateral edema of the basal ganglia (Fig. 1a), of both cerebellar hemispheres (Fig. 1b) as well as the capsula interna (Fig. 1c) with diffusion restriction and apparent diffusion coefficient (ADC) signal reductions and fluid attenuated inversion recovery (FLAIR) imaging revealed hyperintense alterations in those areas. In addition, DWI and FLAIR imaging presented mild, confluent white matter abnormalities above the lateral ventricle (Supplementary figure 1A, B). A time-of-flight (TOF)-angiography was normal. An initial spinal tap and subsequent cerebrospinal fluid analysis revealed a disturbance of the blood-brain barrier but normal total protein (542 mg/l) and normal lymphocyte counts (4/μL) and no intrathecal antibody synthesis. An electroencephalogram (EEG) revealed intermittent deceleration without epileptic discharges.
Fig. 1 MRI imaging on day 1 and day 11 after intoxication. Timepoint 1 (Day 1 after intoxication) DWI sequences: a 1 basal ganglia lesions; b Bilateral cerebellar lesions; c Capsula interna lesions, posterior limb. Timepoint 2 (Day 11 after intoxication) FLAIR sequences: d new lesion at timepoint 2 in crura cerebri; e cerebellar lesions; f Capsula interna lesions, posterior limb
After admission, the patient was continuously awake and responsive and did not require intensive care treatment. Initially, walking was impaired without a need for a walking aid.
A transesophageal echocardiography revealed no cardiac abnormalities and especially no endocarditis. Repeated blood cultures were negative. Ear-nose-throat consultation revealed an injury of the inner ear with a diminished ability to hear below 55 dB. We performed treatment with prednisolone for 3 days (days 7–9) at 1 mg per kilogram body weight, which did not cause any immediate conceivable improvement of hearing but the hearing ability improved continuously. The unsteady gait improved to an almost normal level between days 9–11 of inpatient treatment. In contrast, cognitive deficits remained unchanged with increased response latency, slowed speech and concentration deficits. Additionally, the hypoesthesia of the inner thigh remained unchanged.
An additional MRI after 11 days revealed the known FLAIR-hyperintense lesions of basal ganglia, capsula interna (Fig. 1f) and subtle abnormalities above the lateral ventricles (Supplementary figure 1C, D) as well as the cerebellar hemispheres (Fig. 1e), which were now ADC increased. Interestingly, new lesions were found in the crura cerebri bilaterally (Fig. 1d). Another spinal tap revealed an increase of lymphocytes (11/μl), but otherwise no pathological findings with a normal blood-brain barrier. Flow cytometry analysis of cerebrospinal fluid (CSF) cells revealed a shift in monocyte subtypes with a significant increase of the non-classical CD14 + CD16+ monocyte-fraction and decrease of the CD56bright natural killer cell-fraction in the lymphocyte subset in the CSF (Fig. 2). Reference values had been previously collected from 29 patients (female: 58%, mean age: 24.1y + − 5.0 standard deviation (SD)) with psychsosomatic disorder (exclusion of inflammatory CNS disorder; CSF: less than 5 cells/μl, normal protein, no intrathecal antibody synthesis).
Fig. 2 Flow Cytometry on day 11 after intoxication. Red dots indicating values of the patients, boxplot based on 29 patients with somatoform disorder (mean and 2 SD). 1: Gated cerebral spinal fluid (CSF) results. 2: Gated peripheral blood (BP) results. 3: Total CSF results. 4: Gated CSF results
With improved walking and hearing but considerable neurocognitive impairment we discharged the patient after 13 days to subsequent rehabilitation.
A neuropsychological assessment on day 18 revealed mild-to-moderate overall cognitive impairments when compared with normative data stratified for age and education (Fig. 3, Supplementary Table S1 for raw scores). Particularly tests assessing cognitive processing speed (e.g., TAP, SDMT, TMT, Time to copy a complex figure) showed consistent alterations from the norm. Learning efficiency of both verbal (RAVLT) and visual material (BVMT-R) was also impaired whereas recall from memory was only reduced for verbal but preserved for complex visual material. Interestingly, the patient showed preserved performance in tests for complex attention and higher executive functions such as planning abilities (D-KEFS Tower Test).
Fig. 3 Results of the neuropsychological assessment on day 18 after intoxication. Test parameters are depicted as z-scores stratified for age and education. Negative values indicate worse performance compared to the normative sample. Performances within the dotted area are within 1 SD from the mean of the normative sample (z = 0 +/− 1). Test parameters are grouped into broader cognitive domains (in bold and italics). Mild-to-moderate deficits in tests for cognitive processing speed, verbal learning and memory as well as efficiency of visual learning were observed. MoCA = Montreal Cognitive Assessment; RAVLT = Rey Auditory Verbal Learning Test; BVMT-R = Brief Visual Memory Test Revised; RCFT = Rey Complex Figure Test; SDMT = Symbol Digit Modalities Test; TMT = Trail Making Test (Part A and B); TAP = Test for Attentional Performance; D-KEFS=Delis-Kaplan Executive Functions System
Discussion and conclusions
Here we report a case of intravenous methadone-induced CNS damage that is unusually bi-phasic in presentation when compared to the available literature. The initial stage was characterized by acute-onset focal neurological signs and localized signs of diffuse CNS toxicity including ischemic changes in MRI while the second stage showed a gradual progression of more widespread damage and cognitive deficits with signs of local immune activation. We thus speculate that the initial damage may have triggered secondary intrathecal inflammation.
Compared to previous case reports, which described oral consumption of methadone ranging from 1,28 mg/L [6] to 0,21 mg/L [7], the present patient consumed methadone at a considerably higher dose. This could explain why acute onset neurological changes have been rarely described while delayed onset of methadone-induced encephalopathy is well known [3]. Our patient also consumed methadone not orally but intravenously. Previous reports describe oral ingestion of methadone or oral or inhaled heroine leading to symmetrical leukoencephalopathy [8, 9]. We detected multifocal edema in the basal ganglia, capsula interna and both cerebellar hemispheres which may reflect direct toxicity of the drug or ischemic changes. Interestingly, the affected areas of the brain show highest expression of mu-opioid receptors and therefore potentially high susceptibility to opioid overstimulation [4]. In addition, the described pattern of the lesions showing restricted diffusion, no contrast enhancement and additional affection of deep gray nuclei and corpus callosum have been linked to toxic and metabolic disorders [10] and go beyond the typical presentation of acute toxic leukoencephalopathy [11]. Considering the possible differential diagnosis for toxic or metabolic disorders (e.g. carbon monoxide (CO), hepatic/hyperammonemic encephalopathy, hypoxic-ischemic encephalopathy (HIE), osmotic demyelination syndrome (extra-pontine myelinolysis) and the clinical features and history of the patient, methadone/opiate-induced encephalopathy along with hypoxic-ischemic encephalopathy are the two most probable causes for the described injury.
As the intravenous methadone consumption was only performed at a single point of time, one would expect a decrease in symptoms correlating with the damage seen in radiological imaging as well as CSF. Controversially, this case shows an improvement of clinical findings yet new lesions in the crura cerebri along with a shift in monocyte subtypes and a decrease in the CD56bright NK-cell-fraction in the control exams at day 11. Other cases confirm this clinical course of improved symptoms along with the increasing extent of reduced diffusion imaging after opiate-consumption [11]. However, even though others previously showed a correlation between opiate-related acute toxic leukoencephalopathy and elevation of CSF myelin basic protein suggesting myelin damage [12], the current case report may be the first to present a CSF leukocyte analysis suggesting a secondary inflammatory process.
Our hypothesis of a secondary inflammatory damage is based on surprisingly specific abnormalities in CSF cell composition characterized by a shift of monocytes from classical (CD14 + CD16-) to non-classical (CD14 + CD16+) and shift from CD56bright non killer (NK) cells to CD56dim NK cells. Notably, both CD14 + CD16 + -monocytes and CD56dim NK cells are known pro-inflammatory cell types which may play a role in the delayed encephalopathy [13, 14]. To further support the hypothesis of secondary inflammatory damage against delayed toxic effects one could take a determination of myelin basic protein into consideration, as it has been shown that myelin basic protein can be elevated in acute toxic leukoencephalopathy [12].
We observed persistent neurocognitive impairments at day 18, especially in tests for cognitive processing speed, verbal and visual learning capacity as well as verbal memory recall. This pattern is in line with previous studies reporting a positive association of larger cognitive impairment with higher methadone doses (for a review see [5]). Associations between domain-specific cognitive impairments and local of brain lesions are however highly variable in young patients due to their usually high levels of cognitive reserve and related compensatory mechanisms [15].
In summary, intravenous methadone intoxication may lead to both primary metabolic-toxic as well as diffuse CNS toxicity that could be interpreted as secondary delayed and potentially inflammatory encephalopathy with persistent neurological deficits including neurocognitive impairment.
Supplementary Information
Additional file 1: Supplementary Figure 1. Additional MRI imaging on day 1 and day 11. Timepoint 1 (Day 1 after intoxication): A: DWI sequence above the latter ventricle; B: FLAIR sequence above the latter ventricle Timepoint 2 (Day 11 after intoxication) FLAIR sequences: C: DWI sequence above the latter ventricle; D: FLAIR sequence above the latter ventricle.
Additional file 2: Supplementary Table S1. Raw Scores and z-scores of neuropsychological test results.
Abbreviations
ADCApparent diffusion coefficient
BVMT-RBrief visuospatial memory test-revised
CDCluster of differentiation
CNSCentral nervous system
CSFCerebrospinal fluid
dBDecibel
D-KEFSDelis-Kaplan executive function test
ECGElectrocardiogram
EEGElectroencephalogram
FACSFluorescence-activated cell scanning
FASTFocused assessment with sonography for trauma
FLAIRFluid attenuated inversion recovery
MRIMagnetic resonance imaging
NKNon killer
RAVLTRey auditory verbal learning test
SDStandard deviation
SDMTSymbol digit modalities test
TAPTest of attentional performance
TMTTrail marking test
TOFTime-of-flight
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jonathan Repple and Svea Haessner are first authors.
Acknowledgements
Not applicable.
Authors’ contributions
JR and SEH analyzed and interpreted the patient data and contributed majorly in writing the manuscript. GMzH supervised the data analysis as well as the writing progress and gave guidance. MP contributed to the manuscript. ASM performed the flow cytometric analysis and contributed to the manuscript. NCL executed the neuropsychological examination and joined with AJ to generate the extended neurocognitive evaluation and graphs. AJ also contributed in writing the neuropsychological part of the manuscript. HW contributed significantly to the manuscript. The author(s) read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editors-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33618681 | 18,992,539 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Encephalopathy'. | Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.
BACKGROUND
The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare.
METHODS
Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid.
CONCLUSIONS
This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Background
The mu-opioid agonist methadone is administered orally and is widely used in opioid detoxification and maintenance programs and in the treatment of moderate-to-severe pain in some countries. Oral methadone–use and –abuse have been associated with potential inflammatory and toxic central nervous system (CNS) adverse effects such as cerebellitis [1] and delayed-onset toxic leukoencephalopathy [2–4]. Moreover, cognitive deficits have been reported in long-term methadone users [5]. However, case reports of intravenous methadone application [6] are rare and limited to ischemic changes or hypoxia-induced encephalopathy.
Here, we report a 19-year old male patient who subsequently to recreational intravenous methadone-abuse initially presented with acute neurological deficits with magnetic resonance imaging changes in the bilateral basal ganglia and the cerebellum. Subsequently, the patient developed wide-spread white matter T2-hyperintense lesions and delayed-onset encephalopathy accompanied by signs of secondary inflammation. Cerebral spinal fluid (CSF) flow cytometry revealed an inversion of monocyte and natural killer cell subsets while extensive neuropsychological examination demonstrated persistent cognitive deficits. This suggests a potential sequential toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Case presentation
A 19-year old Caucasian male presented to the University Hospital of Muenster emergency department after being unresponsive for 5 h. After consuming liquid methadone intravenously the night before, the patient awoke and immediately complained of partial bilateral hearing loss, walking impairment and numbness of both inner thighs.
According to third-party history obtained from two accompanying friends (the patient was amnestic regarding the night before) the patient had consumed 3 × 2.5 mL of liquid methadone (produced for substitution therapy) intravenously. They reported observing unconsciousness, urinary incontinence, and a twist of his eyes. The patient and accompanying friends admitted to occasionally orally using illegally obtained methadone and cannabis but credibly denied consuming these substances or other opiods and illegal drugs in the days before. This was the first event of intravenous methadone abuse. The medical history of the patient was otherwise unremarkable.
In the neurological examination the patient presented fluctuating consciousness, severe psychomotor and cognitive slowing (slowed speech, increased response latency, concentration deficits), mild paraparesis of the lower limbs, clonus when testing the left patellar reflex and symmetrical bilateral hypoesthesia of the inner thigh. Medical examination showed a heart rate of 76 beats per minute, blood pressure 121/73 mmHg, peripheral oxygen saturation of 97% and temperature of 36.8 °C. An electrocardiogram (ECG) showed only unspecific change of the ST-segment in V2 and V3. FAST-ultrasound did not reveal any abnormalities.
Blood tests revealed a slightly elevated c-reactive protein (5.2 mg/dl; reference < .5 mg/dl), an elevated GOP (400 U /l; reference: < 30 U/l), GPT (118 U/l; reference < 40 U /l) and an increased creatin-kinase (7104 U/l; reference: < 174 U/l) and lactatdehydrogenase (563 U/l; reference 117–217 U/l). Sodium and potassium levels were within normal range. Intoxication screening of the urine was positive for methadone (2.55 mg/l) and cannabinoids (THC-COOH: 29 μg/l) but was negative for other drugs including non-methadone opioids and barbiturates, benzodiazepines, tricyclic antidepressive drugs, methamphetamines, cocaine, phencyclidine and paracetamol. An initial magnetic resonance imaging (MRI) showed multifocal, bilateral edema of the basal ganglia (Fig. 1a), of both cerebellar hemispheres (Fig. 1b) as well as the capsula interna (Fig. 1c) with diffusion restriction and apparent diffusion coefficient (ADC) signal reductions and fluid attenuated inversion recovery (FLAIR) imaging revealed hyperintense alterations in those areas. In addition, DWI and FLAIR imaging presented mild, confluent white matter abnormalities above the lateral ventricle (Supplementary figure 1A, B). A time-of-flight (TOF)-angiography was normal. An initial spinal tap and subsequent cerebrospinal fluid analysis revealed a disturbance of the blood-brain barrier but normal total protein (542 mg/l) and normal lymphocyte counts (4/μL) and no intrathecal antibody synthesis. An electroencephalogram (EEG) revealed intermittent deceleration without epileptic discharges.
Fig. 1 MRI imaging on day 1 and day 11 after intoxication. Timepoint 1 (Day 1 after intoxication) DWI sequences: a 1 basal ganglia lesions; b Bilateral cerebellar lesions; c Capsula interna lesions, posterior limb. Timepoint 2 (Day 11 after intoxication) FLAIR sequences: d new lesion at timepoint 2 in crura cerebri; e cerebellar lesions; f Capsula interna lesions, posterior limb
After admission, the patient was continuously awake and responsive and did not require intensive care treatment. Initially, walking was impaired without a need for a walking aid.
A transesophageal echocardiography revealed no cardiac abnormalities and especially no endocarditis. Repeated blood cultures were negative. Ear-nose-throat consultation revealed an injury of the inner ear with a diminished ability to hear below 55 dB. We performed treatment with prednisolone for 3 days (days 7–9) at 1 mg per kilogram body weight, which did not cause any immediate conceivable improvement of hearing but the hearing ability improved continuously. The unsteady gait improved to an almost normal level between days 9–11 of inpatient treatment. In contrast, cognitive deficits remained unchanged with increased response latency, slowed speech and concentration deficits. Additionally, the hypoesthesia of the inner thigh remained unchanged.
An additional MRI after 11 days revealed the known FLAIR-hyperintense lesions of basal ganglia, capsula interna (Fig. 1f) and subtle abnormalities above the lateral ventricles (Supplementary figure 1C, D) as well as the cerebellar hemispheres (Fig. 1e), which were now ADC increased. Interestingly, new lesions were found in the crura cerebri bilaterally (Fig. 1d). Another spinal tap revealed an increase of lymphocytes (11/μl), but otherwise no pathological findings with a normal blood-brain barrier. Flow cytometry analysis of cerebrospinal fluid (CSF) cells revealed a shift in monocyte subtypes with a significant increase of the non-classical CD14 + CD16+ monocyte-fraction and decrease of the CD56bright natural killer cell-fraction in the lymphocyte subset in the CSF (Fig. 2). Reference values had been previously collected from 29 patients (female: 58%, mean age: 24.1y + − 5.0 standard deviation (SD)) with psychsosomatic disorder (exclusion of inflammatory CNS disorder; CSF: less than 5 cells/μl, normal protein, no intrathecal antibody synthesis).
Fig. 2 Flow Cytometry on day 11 after intoxication. Red dots indicating values of the patients, boxplot based on 29 patients with somatoform disorder (mean and 2 SD). 1: Gated cerebral spinal fluid (CSF) results. 2: Gated peripheral blood (BP) results. 3: Total CSF results. 4: Gated CSF results
With improved walking and hearing but considerable neurocognitive impairment we discharged the patient after 13 days to subsequent rehabilitation.
A neuropsychological assessment on day 18 revealed mild-to-moderate overall cognitive impairments when compared with normative data stratified for age and education (Fig. 3, Supplementary Table S1 for raw scores). Particularly tests assessing cognitive processing speed (e.g., TAP, SDMT, TMT, Time to copy a complex figure) showed consistent alterations from the norm. Learning efficiency of both verbal (RAVLT) and visual material (BVMT-R) was also impaired whereas recall from memory was only reduced for verbal but preserved for complex visual material. Interestingly, the patient showed preserved performance in tests for complex attention and higher executive functions such as planning abilities (D-KEFS Tower Test).
Fig. 3 Results of the neuropsychological assessment on day 18 after intoxication. Test parameters are depicted as z-scores stratified for age and education. Negative values indicate worse performance compared to the normative sample. Performances within the dotted area are within 1 SD from the mean of the normative sample (z = 0 +/− 1). Test parameters are grouped into broader cognitive domains (in bold and italics). Mild-to-moderate deficits in tests for cognitive processing speed, verbal learning and memory as well as efficiency of visual learning were observed. MoCA = Montreal Cognitive Assessment; RAVLT = Rey Auditory Verbal Learning Test; BVMT-R = Brief Visual Memory Test Revised; RCFT = Rey Complex Figure Test; SDMT = Symbol Digit Modalities Test; TMT = Trail Making Test (Part A and B); TAP = Test for Attentional Performance; D-KEFS=Delis-Kaplan Executive Functions System
Discussion and conclusions
Here we report a case of intravenous methadone-induced CNS damage that is unusually bi-phasic in presentation when compared to the available literature. The initial stage was characterized by acute-onset focal neurological signs and localized signs of diffuse CNS toxicity including ischemic changes in MRI while the second stage showed a gradual progression of more widespread damage and cognitive deficits with signs of local immune activation. We thus speculate that the initial damage may have triggered secondary intrathecal inflammation.
Compared to previous case reports, which described oral consumption of methadone ranging from 1,28 mg/L [6] to 0,21 mg/L [7], the present patient consumed methadone at a considerably higher dose. This could explain why acute onset neurological changes have been rarely described while delayed onset of methadone-induced encephalopathy is well known [3]. Our patient also consumed methadone not orally but intravenously. Previous reports describe oral ingestion of methadone or oral or inhaled heroine leading to symmetrical leukoencephalopathy [8, 9]. We detected multifocal edema in the basal ganglia, capsula interna and both cerebellar hemispheres which may reflect direct toxicity of the drug or ischemic changes. Interestingly, the affected areas of the brain show highest expression of mu-opioid receptors and therefore potentially high susceptibility to opioid overstimulation [4]. In addition, the described pattern of the lesions showing restricted diffusion, no contrast enhancement and additional affection of deep gray nuclei and corpus callosum have been linked to toxic and metabolic disorders [10] and go beyond the typical presentation of acute toxic leukoencephalopathy [11]. Considering the possible differential diagnosis for toxic or metabolic disorders (e.g. carbon monoxide (CO), hepatic/hyperammonemic encephalopathy, hypoxic-ischemic encephalopathy (HIE), osmotic demyelination syndrome (extra-pontine myelinolysis) and the clinical features and history of the patient, methadone/opiate-induced encephalopathy along with hypoxic-ischemic encephalopathy are the two most probable causes for the described injury.
As the intravenous methadone consumption was only performed at a single point of time, one would expect a decrease in symptoms correlating with the damage seen in radiological imaging as well as CSF. Controversially, this case shows an improvement of clinical findings yet new lesions in the crura cerebri along with a shift in monocyte subtypes and a decrease in the CD56bright NK-cell-fraction in the control exams at day 11. Other cases confirm this clinical course of improved symptoms along with the increasing extent of reduced diffusion imaging after opiate-consumption [11]. However, even though others previously showed a correlation between opiate-related acute toxic leukoencephalopathy and elevation of CSF myelin basic protein suggesting myelin damage [12], the current case report may be the first to present a CSF leukocyte analysis suggesting a secondary inflammatory process.
Our hypothesis of a secondary inflammatory damage is based on surprisingly specific abnormalities in CSF cell composition characterized by a shift of monocytes from classical (CD14 + CD16-) to non-classical (CD14 + CD16+) and shift from CD56bright non killer (NK) cells to CD56dim NK cells. Notably, both CD14 + CD16 + -monocytes and CD56dim NK cells are known pro-inflammatory cell types which may play a role in the delayed encephalopathy [13, 14]. To further support the hypothesis of secondary inflammatory damage against delayed toxic effects one could take a determination of myelin basic protein into consideration, as it has been shown that myelin basic protein can be elevated in acute toxic leukoencephalopathy [12].
We observed persistent neurocognitive impairments at day 18, especially in tests for cognitive processing speed, verbal and visual learning capacity as well as verbal memory recall. This pattern is in line with previous studies reporting a positive association of larger cognitive impairment with higher methadone doses (for a review see [5]). Associations between domain-specific cognitive impairments and local of brain lesions are however highly variable in young patients due to their usually high levels of cognitive reserve and related compensatory mechanisms [15].
In summary, intravenous methadone intoxication may lead to both primary metabolic-toxic as well as diffuse CNS toxicity that could be interpreted as secondary delayed and potentially inflammatory encephalopathy with persistent neurological deficits including neurocognitive impairment.
Supplementary Information
Additional file 1: Supplementary Figure 1. Additional MRI imaging on day 1 and day 11. Timepoint 1 (Day 1 after intoxication): A: DWI sequence above the latter ventricle; B: FLAIR sequence above the latter ventricle Timepoint 2 (Day 11 after intoxication) FLAIR sequences: C: DWI sequence above the latter ventricle; D: FLAIR sequence above the latter ventricle.
Additional file 2: Supplementary Table S1. Raw Scores and z-scores of neuropsychological test results.
Abbreviations
ADCApparent diffusion coefficient
BVMT-RBrief visuospatial memory test-revised
CDCluster of differentiation
CNSCentral nervous system
CSFCerebrospinal fluid
dBDecibel
D-KEFSDelis-Kaplan executive function test
ECGElectrocardiogram
EEGElectroencephalogram
FACSFluorescence-activated cell scanning
FASTFocused assessment with sonography for trauma
FLAIRFluid attenuated inversion recovery
MRIMagnetic resonance imaging
NKNon killer
RAVLTRey auditory verbal learning test
SDStandard deviation
SDMTSymbol digit modalities test
TAPTest of attentional performance
TMTTrail marking test
TOFTime-of-flight
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jonathan Repple and Svea Haessner are first authors.
Acknowledgements
Not applicable.
Authors’ contributions
JR and SEH analyzed and interpreted the patient data and contributed majorly in writing the manuscript. GMzH supervised the data analysis as well as the writing progress and gave guidance. MP contributed to the manuscript. ASM performed the flow cytometric analysis and contributed to the manuscript. NCL executed the neuropsychological examination and joined with AJ to generate the extended neurocognitive evaluation and graphs. AJ also contributed in writing the neuropsychological part of the manuscript. HW contributed significantly to the manuscript. The author(s) read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editors-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33618681 | 18,992,539 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoxic-ischaemic encephalopathy'. | Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.
BACKGROUND
The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare.
METHODS
Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid.
CONCLUSIONS
This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Background
The mu-opioid agonist methadone is administered orally and is widely used in opioid detoxification and maintenance programs and in the treatment of moderate-to-severe pain in some countries. Oral methadone–use and –abuse have been associated with potential inflammatory and toxic central nervous system (CNS) adverse effects such as cerebellitis [1] and delayed-onset toxic leukoencephalopathy [2–4]. Moreover, cognitive deficits have been reported in long-term methadone users [5]. However, case reports of intravenous methadone application [6] are rare and limited to ischemic changes or hypoxia-induced encephalopathy.
Here, we report a 19-year old male patient who subsequently to recreational intravenous methadone-abuse initially presented with acute neurological deficits with magnetic resonance imaging changes in the bilateral basal ganglia and the cerebellum. Subsequently, the patient developed wide-spread white matter T2-hyperintense lesions and delayed-onset encephalopathy accompanied by signs of secondary inflammation. Cerebral spinal fluid (CSF) flow cytometry revealed an inversion of monocyte and natural killer cell subsets while extensive neuropsychological examination demonstrated persistent cognitive deficits. This suggests a potential sequential toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Case presentation
A 19-year old Caucasian male presented to the University Hospital of Muenster emergency department after being unresponsive for 5 h. After consuming liquid methadone intravenously the night before, the patient awoke and immediately complained of partial bilateral hearing loss, walking impairment and numbness of both inner thighs.
According to third-party history obtained from two accompanying friends (the patient was amnestic regarding the night before) the patient had consumed 3 × 2.5 mL of liquid methadone (produced for substitution therapy) intravenously. They reported observing unconsciousness, urinary incontinence, and a twist of his eyes. The patient and accompanying friends admitted to occasionally orally using illegally obtained methadone and cannabis but credibly denied consuming these substances or other opiods and illegal drugs in the days before. This was the first event of intravenous methadone abuse. The medical history of the patient was otherwise unremarkable.
In the neurological examination the patient presented fluctuating consciousness, severe psychomotor and cognitive slowing (slowed speech, increased response latency, concentration deficits), mild paraparesis of the lower limbs, clonus when testing the left patellar reflex and symmetrical bilateral hypoesthesia of the inner thigh. Medical examination showed a heart rate of 76 beats per minute, blood pressure 121/73 mmHg, peripheral oxygen saturation of 97% and temperature of 36.8 °C. An electrocardiogram (ECG) showed only unspecific change of the ST-segment in V2 and V3. FAST-ultrasound did not reveal any abnormalities.
Blood tests revealed a slightly elevated c-reactive protein (5.2 mg/dl; reference < .5 mg/dl), an elevated GOP (400 U /l; reference: < 30 U/l), GPT (118 U/l; reference < 40 U /l) and an increased creatin-kinase (7104 U/l; reference: < 174 U/l) and lactatdehydrogenase (563 U/l; reference 117–217 U/l). Sodium and potassium levels were within normal range. Intoxication screening of the urine was positive for methadone (2.55 mg/l) and cannabinoids (THC-COOH: 29 μg/l) but was negative for other drugs including non-methadone opioids and barbiturates, benzodiazepines, tricyclic antidepressive drugs, methamphetamines, cocaine, phencyclidine and paracetamol. An initial magnetic resonance imaging (MRI) showed multifocal, bilateral edema of the basal ganglia (Fig. 1a), of both cerebellar hemispheres (Fig. 1b) as well as the capsula interna (Fig. 1c) with diffusion restriction and apparent diffusion coefficient (ADC) signal reductions and fluid attenuated inversion recovery (FLAIR) imaging revealed hyperintense alterations in those areas. In addition, DWI and FLAIR imaging presented mild, confluent white matter abnormalities above the lateral ventricle (Supplementary figure 1A, B). A time-of-flight (TOF)-angiography was normal. An initial spinal tap and subsequent cerebrospinal fluid analysis revealed a disturbance of the blood-brain barrier but normal total protein (542 mg/l) and normal lymphocyte counts (4/μL) and no intrathecal antibody synthesis. An electroencephalogram (EEG) revealed intermittent deceleration without epileptic discharges.
Fig. 1 MRI imaging on day 1 and day 11 after intoxication. Timepoint 1 (Day 1 after intoxication) DWI sequences: a 1 basal ganglia lesions; b Bilateral cerebellar lesions; c Capsula interna lesions, posterior limb. Timepoint 2 (Day 11 after intoxication) FLAIR sequences: d new lesion at timepoint 2 in crura cerebri; e cerebellar lesions; f Capsula interna lesions, posterior limb
After admission, the patient was continuously awake and responsive and did not require intensive care treatment. Initially, walking was impaired without a need for a walking aid.
A transesophageal echocardiography revealed no cardiac abnormalities and especially no endocarditis. Repeated blood cultures were negative. Ear-nose-throat consultation revealed an injury of the inner ear with a diminished ability to hear below 55 dB. We performed treatment with prednisolone for 3 days (days 7–9) at 1 mg per kilogram body weight, which did not cause any immediate conceivable improvement of hearing but the hearing ability improved continuously. The unsteady gait improved to an almost normal level between days 9–11 of inpatient treatment. In contrast, cognitive deficits remained unchanged with increased response latency, slowed speech and concentration deficits. Additionally, the hypoesthesia of the inner thigh remained unchanged.
An additional MRI after 11 days revealed the known FLAIR-hyperintense lesions of basal ganglia, capsula interna (Fig. 1f) and subtle abnormalities above the lateral ventricles (Supplementary figure 1C, D) as well as the cerebellar hemispheres (Fig. 1e), which were now ADC increased. Interestingly, new lesions were found in the crura cerebri bilaterally (Fig. 1d). Another spinal tap revealed an increase of lymphocytes (11/μl), but otherwise no pathological findings with a normal blood-brain barrier. Flow cytometry analysis of cerebrospinal fluid (CSF) cells revealed a shift in monocyte subtypes with a significant increase of the non-classical CD14 + CD16+ monocyte-fraction and decrease of the CD56bright natural killer cell-fraction in the lymphocyte subset in the CSF (Fig. 2). Reference values had been previously collected from 29 patients (female: 58%, mean age: 24.1y + − 5.0 standard deviation (SD)) with psychsosomatic disorder (exclusion of inflammatory CNS disorder; CSF: less than 5 cells/μl, normal protein, no intrathecal antibody synthesis).
Fig. 2 Flow Cytometry on day 11 after intoxication. Red dots indicating values of the patients, boxplot based on 29 patients with somatoform disorder (mean and 2 SD). 1: Gated cerebral spinal fluid (CSF) results. 2: Gated peripheral blood (BP) results. 3: Total CSF results. 4: Gated CSF results
With improved walking and hearing but considerable neurocognitive impairment we discharged the patient after 13 days to subsequent rehabilitation.
A neuropsychological assessment on day 18 revealed mild-to-moderate overall cognitive impairments when compared with normative data stratified for age and education (Fig. 3, Supplementary Table S1 for raw scores). Particularly tests assessing cognitive processing speed (e.g., TAP, SDMT, TMT, Time to copy a complex figure) showed consistent alterations from the norm. Learning efficiency of both verbal (RAVLT) and visual material (BVMT-R) was also impaired whereas recall from memory was only reduced for verbal but preserved for complex visual material. Interestingly, the patient showed preserved performance in tests for complex attention and higher executive functions such as planning abilities (D-KEFS Tower Test).
Fig. 3 Results of the neuropsychological assessment on day 18 after intoxication. Test parameters are depicted as z-scores stratified for age and education. Negative values indicate worse performance compared to the normative sample. Performances within the dotted area are within 1 SD from the mean of the normative sample (z = 0 +/− 1). Test parameters are grouped into broader cognitive domains (in bold and italics). Mild-to-moderate deficits in tests for cognitive processing speed, verbal learning and memory as well as efficiency of visual learning were observed. MoCA = Montreal Cognitive Assessment; RAVLT = Rey Auditory Verbal Learning Test; BVMT-R = Brief Visual Memory Test Revised; RCFT = Rey Complex Figure Test; SDMT = Symbol Digit Modalities Test; TMT = Trail Making Test (Part A and B); TAP = Test for Attentional Performance; D-KEFS=Delis-Kaplan Executive Functions System
Discussion and conclusions
Here we report a case of intravenous methadone-induced CNS damage that is unusually bi-phasic in presentation when compared to the available literature. The initial stage was characterized by acute-onset focal neurological signs and localized signs of diffuse CNS toxicity including ischemic changes in MRI while the second stage showed a gradual progression of more widespread damage and cognitive deficits with signs of local immune activation. We thus speculate that the initial damage may have triggered secondary intrathecal inflammation.
Compared to previous case reports, which described oral consumption of methadone ranging from 1,28 mg/L [6] to 0,21 mg/L [7], the present patient consumed methadone at a considerably higher dose. This could explain why acute onset neurological changes have been rarely described while delayed onset of methadone-induced encephalopathy is well known [3]. Our patient also consumed methadone not orally but intravenously. Previous reports describe oral ingestion of methadone or oral or inhaled heroine leading to symmetrical leukoencephalopathy [8, 9]. We detected multifocal edema in the basal ganglia, capsula interna and both cerebellar hemispheres which may reflect direct toxicity of the drug or ischemic changes. Interestingly, the affected areas of the brain show highest expression of mu-opioid receptors and therefore potentially high susceptibility to opioid overstimulation [4]. In addition, the described pattern of the lesions showing restricted diffusion, no contrast enhancement and additional affection of deep gray nuclei and corpus callosum have been linked to toxic and metabolic disorders [10] and go beyond the typical presentation of acute toxic leukoencephalopathy [11]. Considering the possible differential diagnosis for toxic or metabolic disorders (e.g. carbon monoxide (CO), hepatic/hyperammonemic encephalopathy, hypoxic-ischemic encephalopathy (HIE), osmotic demyelination syndrome (extra-pontine myelinolysis) and the clinical features and history of the patient, methadone/opiate-induced encephalopathy along with hypoxic-ischemic encephalopathy are the two most probable causes for the described injury.
As the intravenous methadone consumption was only performed at a single point of time, one would expect a decrease in symptoms correlating with the damage seen in radiological imaging as well as CSF. Controversially, this case shows an improvement of clinical findings yet new lesions in the crura cerebri along with a shift in monocyte subtypes and a decrease in the CD56bright NK-cell-fraction in the control exams at day 11. Other cases confirm this clinical course of improved symptoms along with the increasing extent of reduced diffusion imaging after opiate-consumption [11]. However, even though others previously showed a correlation between opiate-related acute toxic leukoencephalopathy and elevation of CSF myelin basic protein suggesting myelin damage [12], the current case report may be the first to present a CSF leukocyte analysis suggesting a secondary inflammatory process.
Our hypothesis of a secondary inflammatory damage is based on surprisingly specific abnormalities in CSF cell composition characterized by a shift of monocytes from classical (CD14 + CD16-) to non-classical (CD14 + CD16+) and shift from CD56bright non killer (NK) cells to CD56dim NK cells. Notably, both CD14 + CD16 + -monocytes and CD56dim NK cells are known pro-inflammatory cell types which may play a role in the delayed encephalopathy [13, 14]. To further support the hypothesis of secondary inflammatory damage against delayed toxic effects one could take a determination of myelin basic protein into consideration, as it has been shown that myelin basic protein can be elevated in acute toxic leukoencephalopathy [12].
We observed persistent neurocognitive impairments at day 18, especially in tests for cognitive processing speed, verbal and visual learning capacity as well as verbal memory recall. This pattern is in line with previous studies reporting a positive association of larger cognitive impairment with higher methadone doses (for a review see [5]). Associations between domain-specific cognitive impairments and local of brain lesions are however highly variable in young patients due to their usually high levels of cognitive reserve and related compensatory mechanisms [15].
In summary, intravenous methadone intoxication may lead to both primary metabolic-toxic as well as diffuse CNS toxicity that could be interpreted as secondary delayed and potentially inflammatory encephalopathy with persistent neurological deficits including neurocognitive impairment.
Supplementary Information
Additional file 1: Supplementary Figure 1. Additional MRI imaging on day 1 and day 11. Timepoint 1 (Day 1 after intoxication): A: DWI sequence above the latter ventricle; B: FLAIR sequence above the latter ventricle Timepoint 2 (Day 11 after intoxication) FLAIR sequences: C: DWI sequence above the latter ventricle; D: FLAIR sequence above the latter ventricle.
Additional file 2: Supplementary Table S1. Raw Scores and z-scores of neuropsychological test results.
Abbreviations
ADCApparent diffusion coefficient
BVMT-RBrief visuospatial memory test-revised
CDCluster of differentiation
CNSCentral nervous system
CSFCerebrospinal fluid
dBDecibel
D-KEFSDelis-Kaplan executive function test
ECGElectrocardiogram
EEGElectroencephalogram
FACSFluorescence-activated cell scanning
FASTFocused assessment with sonography for trauma
FLAIRFluid attenuated inversion recovery
MRIMagnetic resonance imaging
NKNon killer
RAVLTRey auditory verbal learning test
SDStandard deviation
SDMTSymbol digit modalities test
TAPTest of attentional performance
TMTTrail marking test
TOFTime-of-flight
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jonathan Repple and Svea Haessner are first authors.
Acknowledgements
Not applicable.
Authors’ contributions
JR and SEH analyzed and interpreted the patient data and contributed majorly in writing the manuscript. GMzH supervised the data analysis as well as the writing progress and gave guidance. MP contributed to the manuscript. ASM performed the flow cytometric analysis and contributed to the manuscript. NCL executed the neuropsychological examination and joined with AJ to generate the extended neurocognitive evaluation and graphs. AJ also contributed in writing the neuropsychological part of the manuscript. HW contributed significantly to the manuscript. The author(s) read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editors-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33618681 | 18,992,539 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.
BACKGROUND
The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare.
METHODS
Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid.
CONCLUSIONS
This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Background
The mu-opioid agonist methadone is administered orally and is widely used in opioid detoxification and maintenance programs and in the treatment of moderate-to-severe pain in some countries. Oral methadone–use and –abuse have been associated with potential inflammatory and toxic central nervous system (CNS) adverse effects such as cerebellitis [1] and delayed-onset toxic leukoencephalopathy [2–4]. Moreover, cognitive deficits have been reported in long-term methadone users [5]. However, case reports of intravenous methadone application [6] are rare and limited to ischemic changes or hypoxia-induced encephalopathy.
Here, we report a 19-year old male patient who subsequently to recreational intravenous methadone-abuse initially presented with acute neurological deficits with magnetic resonance imaging changes in the bilateral basal ganglia and the cerebellum. Subsequently, the patient developed wide-spread white matter T2-hyperintense lesions and delayed-onset encephalopathy accompanied by signs of secondary inflammation. Cerebral spinal fluid (CSF) flow cytometry revealed an inversion of monocyte and natural killer cell subsets while extensive neuropsychological examination demonstrated persistent cognitive deficits. This suggests a potential sequential toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Case presentation
A 19-year old Caucasian male presented to the University Hospital of Muenster emergency department after being unresponsive for 5 h. After consuming liquid methadone intravenously the night before, the patient awoke and immediately complained of partial bilateral hearing loss, walking impairment and numbness of both inner thighs.
According to third-party history obtained from two accompanying friends (the patient was amnestic regarding the night before) the patient had consumed 3 × 2.5 mL of liquid methadone (produced for substitution therapy) intravenously. They reported observing unconsciousness, urinary incontinence, and a twist of his eyes. The patient and accompanying friends admitted to occasionally orally using illegally obtained methadone and cannabis but credibly denied consuming these substances or other opiods and illegal drugs in the days before. This was the first event of intravenous methadone abuse. The medical history of the patient was otherwise unremarkable.
In the neurological examination the patient presented fluctuating consciousness, severe psychomotor and cognitive slowing (slowed speech, increased response latency, concentration deficits), mild paraparesis of the lower limbs, clonus when testing the left patellar reflex and symmetrical bilateral hypoesthesia of the inner thigh. Medical examination showed a heart rate of 76 beats per minute, blood pressure 121/73 mmHg, peripheral oxygen saturation of 97% and temperature of 36.8 °C. An electrocardiogram (ECG) showed only unspecific change of the ST-segment in V2 and V3. FAST-ultrasound did not reveal any abnormalities.
Blood tests revealed a slightly elevated c-reactive protein (5.2 mg/dl; reference < .5 mg/dl), an elevated GOP (400 U /l; reference: < 30 U/l), GPT (118 U/l; reference < 40 U /l) and an increased creatin-kinase (7104 U/l; reference: < 174 U/l) and lactatdehydrogenase (563 U/l; reference 117–217 U/l). Sodium and potassium levels were within normal range. Intoxication screening of the urine was positive for methadone (2.55 mg/l) and cannabinoids (THC-COOH: 29 μg/l) but was negative for other drugs including non-methadone opioids and barbiturates, benzodiazepines, tricyclic antidepressive drugs, methamphetamines, cocaine, phencyclidine and paracetamol. An initial magnetic resonance imaging (MRI) showed multifocal, bilateral edema of the basal ganglia (Fig. 1a), of both cerebellar hemispheres (Fig. 1b) as well as the capsula interna (Fig. 1c) with diffusion restriction and apparent diffusion coefficient (ADC) signal reductions and fluid attenuated inversion recovery (FLAIR) imaging revealed hyperintense alterations in those areas. In addition, DWI and FLAIR imaging presented mild, confluent white matter abnormalities above the lateral ventricle (Supplementary figure 1A, B). A time-of-flight (TOF)-angiography was normal. An initial spinal tap and subsequent cerebrospinal fluid analysis revealed a disturbance of the blood-brain barrier but normal total protein (542 mg/l) and normal lymphocyte counts (4/μL) and no intrathecal antibody synthesis. An electroencephalogram (EEG) revealed intermittent deceleration without epileptic discharges.
Fig. 1 MRI imaging on day 1 and day 11 after intoxication. Timepoint 1 (Day 1 after intoxication) DWI sequences: a 1 basal ganglia lesions; b Bilateral cerebellar lesions; c Capsula interna lesions, posterior limb. Timepoint 2 (Day 11 after intoxication) FLAIR sequences: d new lesion at timepoint 2 in crura cerebri; e cerebellar lesions; f Capsula interna lesions, posterior limb
After admission, the patient was continuously awake and responsive and did not require intensive care treatment. Initially, walking was impaired without a need for a walking aid.
A transesophageal echocardiography revealed no cardiac abnormalities and especially no endocarditis. Repeated blood cultures were negative. Ear-nose-throat consultation revealed an injury of the inner ear with a diminished ability to hear below 55 dB. We performed treatment with prednisolone for 3 days (days 7–9) at 1 mg per kilogram body weight, which did not cause any immediate conceivable improvement of hearing but the hearing ability improved continuously. The unsteady gait improved to an almost normal level between days 9–11 of inpatient treatment. In contrast, cognitive deficits remained unchanged with increased response latency, slowed speech and concentration deficits. Additionally, the hypoesthesia of the inner thigh remained unchanged.
An additional MRI after 11 days revealed the known FLAIR-hyperintense lesions of basal ganglia, capsula interna (Fig. 1f) and subtle abnormalities above the lateral ventricles (Supplementary figure 1C, D) as well as the cerebellar hemispheres (Fig. 1e), which were now ADC increased. Interestingly, new lesions were found in the crura cerebri bilaterally (Fig. 1d). Another spinal tap revealed an increase of lymphocytes (11/μl), but otherwise no pathological findings with a normal blood-brain barrier. Flow cytometry analysis of cerebrospinal fluid (CSF) cells revealed a shift in monocyte subtypes with a significant increase of the non-classical CD14 + CD16+ monocyte-fraction and decrease of the CD56bright natural killer cell-fraction in the lymphocyte subset in the CSF (Fig. 2). Reference values had been previously collected from 29 patients (female: 58%, mean age: 24.1y + − 5.0 standard deviation (SD)) with psychsosomatic disorder (exclusion of inflammatory CNS disorder; CSF: less than 5 cells/μl, normal protein, no intrathecal antibody synthesis).
Fig. 2 Flow Cytometry on day 11 after intoxication. Red dots indicating values of the patients, boxplot based on 29 patients with somatoform disorder (mean and 2 SD). 1: Gated cerebral spinal fluid (CSF) results. 2: Gated peripheral blood (BP) results. 3: Total CSF results. 4: Gated CSF results
With improved walking and hearing but considerable neurocognitive impairment we discharged the patient after 13 days to subsequent rehabilitation.
A neuropsychological assessment on day 18 revealed mild-to-moderate overall cognitive impairments when compared with normative data stratified for age and education (Fig. 3, Supplementary Table S1 for raw scores). Particularly tests assessing cognitive processing speed (e.g., TAP, SDMT, TMT, Time to copy a complex figure) showed consistent alterations from the norm. Learning efficiency of both verbal (RAVLT) and visual material (BVMT-R) was also impaired whereas recall from memory was only reduced for verbal but preserved for complex visual material. Interestingly, the patient showed preserved performance in tests for complex attention and higher executive functions such as planning abilities (D-KEFS Tower Test).
Fig. 3 Results of the neuropsychological assessment on day 18 after intoxication. Test parameters are depicted as z-scores stratified for age and education. Negative values indicate worse performance compared to the normative sample. Performances within the dotted area are within 1 SD from the mean of the normative sample (z = 0 +/− 1). Test parameters are grouped into broader cognitive domains (in bold and italics). Mild-to-moderate deficits in tests for cognitive processing speed, verbal learning and memory as well as efficiency of visual learning were observed. MoCA = Montreal Cognitive Assessment; RAVLT = Rey Auditory Verbal Learning Test; BVMT-R = Brief Visual Memory Test Revised; RCFT = Rey Complex Figure Test; SDMT = Symbol Digit Modalities Test; TMT = Trail Making Test (Part A and B); TAP = Test for Attentional Performance; D-KEFS=Delis-Kaplan Executive Functions System
Discussion and conclusions
Here we report a case of intravenous methadone-induced CNS damage that is unusually bi-phasic in presentation when compared to the available literature. The initial stage was characterized by acute-onset focal neurological signs and localized signs of diffuse CNS toxicity including ischemic changes in MRI while the second stage showed a gradual progression of more widespread damage and cognitive deficits with signs of local immune activation. We thus speculate that the initial damage may have triggered secondary intrathecal inflammation.
Compared to previous case reports, which described oral consumption of methadone ranging from 1,28 mg/L [6] to 0,21 mg/L [7], the present patient consumed methadone at a considerably higher dose. This could explain why acute onset neurological changes have been rarely described while delayed onset of methadone-induced encephalopathy is well known [3]. Our patient also consumed methadone not orally but intravenously. Previous reports describe oral ingestion of methadone or oral or inhaled heroine leading to symmetrical leukoencephalopathy [8, 9]. We detected multifocal edema in the basal ganglia, capsula interna and both cerebellar hemispheres which may reflect direct toxicity of the drug or ischemic changes. Interestingly, the affected areas of the brain show highest expression of mu-opioid receptors and therefore potentially high susceptibility to opioid overstimulation [4]. In addition, the described pattern of the lesions showing restricted diffusion, no contrast enhancement and additional affection of deep gray nuclei and corpus callosum have been linked to toxic and metabolic disorders [10] and go beyond the typical presentation of acute toxic leukoencephalopathy [11]. Considering the possible differential diagnosis for toxic or metabolic disorders (e.g. carbon monoxide (CO), hepatic/hyperammonemic encephalopathy, hypoxic-ischemic encephalopathy (HIE), osmotic demyelination syndrome (extra-pontine myelinolysis) and the clinical features and history of the patient, methadone/opiate-induced encephalopathy along with hypoxic-ischemic encephalopathy are the two most probable causes for the described injury.
As the intravenous methadone consumption was only performed at a single point of time, one would expect a decrease in symptoms correlating with the damage seen in radiological imaging as well as CSF. Controversially, this case shows an improvement of clinical findings yet new lesions in the crura cerebri along with a shift in monocyte subtypes and a decrease in the CD56bright NK-cell-fraction in the control exams at day 11. Other cases confirm this clinical course of improved symptoms along with the increasing extent of reduced diffusion imaging after opiate-consumption [11]. However, even though others previously showed a correlation between opiate-related acute toxic leukoencephalopathy and elevation of CSF myelin basic protein suggesting myelin damage [12], the current case report may be the first to present a CSF leukocyte analysis suggesting a secondary inflammatory process.
Our hypothesis of a secondary inflammatory damage is based on surprisingly specific abnormalities in CSF cell composition characterized by a shift of monocytes from classical (CD14 + CD16-) to non-classical (CD14 + CD16+) and shift from CD56bright non killer (NK) cells to CD56dim NK cells. Notably, both CD14 + CD16 + -monocytes and CD56dim NK cells are known pro-inflammatory cell types which may play a role in the delayed encephalopathy [13, 14]. To further support the hypothesis of secondary inflammatory damage against delayed toxic effects one could take a determination of myelin basic protein into consideration, as it has been shown that myelin basic protein can be elevated in acute toxic leukoencephalopathy [12].
We observed persistent neurocognitive impairments at day 18, especially in tests for cognitive processing speed, verbal and visual learning capacity as well as verbal memory recall. This pattern is in line with previous studies reporting a positive association of larger cognitive impairment with higher methadone doses (for a review see [5]). Associations between domain-specific cognitive impairments and local of brain lesions are however highly variable in young patients due to their usually high levels of cognitive reserve and related compensatory mechanisms [15].
In summary, intravenous methadone intoxication may lead to both primary metabolic-toxic as well as diffuse CNS toxicity that could be interpreted as secondary delayed and potentially inflammatory encephalopathy with persistent neurological deficits including neurocognitive impairment.
Supplementary Information
Additional file 1: Supplementary Figure 1. Additional MRI imaging on day 1 and day 11. Timepoint 1 (Day 1 after intoxication): A: DWI sequence above the latter ventricle; B: FLAIR sequence above the latter ventricle Timepoint 2 (Day 11 after intoxication) FLAIR sequences: C: DWI sequence above the latter ventricle; D: FLAIR sequence above the latter ventricle.
Additional file 2: Supplementary Table S1. Raw Scores and z-scores of neuropsychological test results.
Abbreviations
ADCApparent diffusion coefficient
BVMT-RBrief visuospatial memory test-revised
CDCluster of differentiation
CNSCentral nervous system
CSFCerebrospinal fluid
dBDecibel
D-KEFSDelis-Kaplan executive function test
ECGElectrocardiogram
EEGElectroencephalogram
FACSFluorescence-activated cell scanning
FASTFocused assessment with sonography for trauma
FLAIRFluid attenuated inversion recovery
MRIMagnetic resonance imaging
NKNon killer
RAVLTRey auditory verbal learning test
SDStandard deviation
SDMTSymbol digit modalities test
TAPTest of attentional performance
TMTTrail marking test
TOFTime-of-flight
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jonathan Repple and Svea Haessner are first authors.
Acknowledgements
Not applicable.
Authors’ contributions
JR and SEH analyzed and interpreted the patient data and contributed majorly in writing the manuscript. GMzH supervised the data analysis as well as the writing progress and gave guidance. MP contributed to the manuscript. ASM performed the flow cytometric analysis and contributed to the manuscript. NCL executed the neuropsychological examination and joined with AJ to generate the extended neurocognitive evaluation and graphs. AJ also contributed in writing the neuropsychological part of the manuscript. HW contributed significantly to the manuscript. The author(s) read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editors-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33618681 | 18,992,539 | 2021-02-22 |
What was the administration route of drug 'METHADONE HYDROCHLORIDE'? | Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.
BACKGROUND
The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare.
METHODS
Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid.
CONCLUSIONS
This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Background
The mu-opioid agonist methadone is administered orally and is widely used in opioid detoxification and maintenance programs and in the treatment of moderate-to-severe pain in some countries. Oral methadone–use and –abuse have been associated with potential inflammatory and toxic central nervous system (CNS) adverse effects such as cerebellitis [1] and delayed-onset toxic leukoencephalopathy [2–4]. Moreover, cognitive deficits have been reported in long-term methadone users [5]. However, case reports of intravenous methadone application [6] are rare and limited to ischemic changes or hypoxia-induced encephalopathy.
Here, we report a 19-year old male patient who subsequently to recreational intravenous methadone-abuse initially presented with acute neurological deficits with magnetic resonance imaging changes in the bilateral basal ganglia and the cerebellum. Subsequently, the patient developed wide-spread white matter T2-hyperintense lesions and delayed-onset encephalopathy accompanied by signs of secondary inflammation. Cerebral spinal fluid (CSF) flow cytometry revealed an inversion of monocyte and natural killer cell subsets while extensive neuropsychological examination demonstrated persistent cognitive deficits. This suggests a potential sequential toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Case presentation
A 19-year old Caucasian male presented to the University Hospital of Muenster emergency department after being unresponsive for 5 h. After consuming liquid methadone intravenously the night before, the patient awoke and immediately complained of partial bilateral hearing loss, walking impairment and numbness of both inner thighs.
According to third-party history obtained from two accompanying friends (the patient was amnestic regarding the night before) the patient had consumed 3 × 2.5 mL of liquid methadone (produced for substitution therapy) intravenously. They reported observing unconsciousness, urinary incontinence, and a twist of his eyes. The patient and accompanying friends admitted to occasionally orally using illegally obtained methadone and cannabis but credibly denied consuming these substances or other opiods and illegal drugs in the days before. This was the first event of intravenous methadone abuse. The medical history of the patient was otherwise unremarkable.
In the neurological examination the patient presented fluctuating consciousness, severe psychomotor and cognitive slowing (slowed speech, increased response latency, concentration deficits), mild paraparesis of the lower limbs, clonus when testing the left patellar reflex and symmetrical bilateral hypoesthesia of the inner thigh. Medical examination showed a heart rate of 76 beats per minute, blood pressure 121/73 mmHg, peripheral oxygen saturation of 97% and temperature of 36.8 °C. An electrocardiogram (ECG) showed only unspecific change of the ST-segment in V2 and V3. FAST-ultrasound did not reveal any abnormalities.
Blood tests revealed a slightly elevated c-reactive protein (5.2 mg/dl; reference < .5 mg/dl), an elevated GOP (400 U /l; reference: < 30 U/l), GPT (118 U/l; reference < 40 U /l) and an increased creatin-kinase (7104 U/l; reference: < 174 U/l) and lactatdehydrogenase (563 U/l; reference 117–217 U/l). Sodium and potassium levels were within normal range. Intoxication screening of the urine was positive for methadone (2.55 mg/l) and cannabinoids (THC-COOH: 29 μg/l) but was negative for other drugs including non-methadone opioids and barbiturates, benzodiazepines, tricyclic antidepressive drugs, methamphetamines, cocaine, phencyclidine and paracetamol. An initial magnetic resonance imaging (MRI) showed multifocal, bilateral edema of the basal ganglia (Fig. 1a), of both cerebellar hemispheres (Fig. 1b) as well as the capsula interna (Fig. 1c) with diffusion restriction and apparent diffusion coefficient (ADC) signal reductions and fluid attenuated inversion recovery (FLAIR) imaging revealed hyperintense alterations in those areas. In addition, DWI and FLAIR imaging presented mild, confluent white matter abnormalities above the lateral ventricle (Supplementary figure 1A, B). A time-of-flight (TOF)-angiography was normal. An initial spinal tap and subsequent cerebrospinal fluid analysis revealed a disturbance of the blood-brain barrier but normal total protein (542 mg/l) and normal lymphocyte counts (4/μL) and no intrathecal antibody synthesis. An electroencephalogram (EEG) revealed intermittent deceleration without epileptic discharges.
Fig. 1 MRI imaging on day 1 and day 11 after intoxication. Timepoint 1 (Day 1 after intoxication) DWI sequences: a 1 basal ganglia lesions; b Bilateral cerebellar lesions; c Capsula interna lesions, posterior limb. Timepoint 2 (Day 11 after intoxication) FLAIR sequences: d new lesion at timepoint 2 in crura cerebri; e cerebellar lesions; f Capsula interna lesions, posterior limb
After admission, the patient was continuously awake and responsive and did not require intensive care treatment. Initially, walking was impaired without a need for a walking aid.
A transesophageal echocardiography revealed no cardiac abnormalities and especially no endocarditis. Repeated blood cultures were negative. Ear-nose-throat consultation revealed an injury of the inner ear with a diminished ability to hear below 55 dB. We performed treatment with prednisolone for 3 days (days 7–9) at 1 mg per kilogram body weight, which did not cause any immediate conceivable improvement of hearing but the hearing ability improved continuously. The unsteady gait improved to an almost normal level between days 9–11 of inpatient treatment. In contrast, cognitive deficits remained unchanged with increased response latency, slowed speech and concentration deficits. Additionally, the hypoesthesia of the inner thigh remained unchanged.
An additional MRI after 11 days revealed the known FLAIR-hyperintense lesions of basal ganglia, capsula interna (Fig. 1f) and subtle abnormalities above the lateral ventricles (Supplementary figure 1C, D) as well as the cerebellar hemispheres (Fig. 1e), which were now ADC increased. Interestingly, new lesions were found in the crura cerebri bilaterally (Fig. 1d). Another spinal tap revealed an increase of lymphocytes (11/μl), but otherwise no pathological findings with a normal blood-brain barrier. Flow cytometry analysis of cerebrospinal fluid (CSF) cells revealed a shift in monocyte subtypes with a significant increase of the non-classical CD14 + CD16+ monocyte-fraction and decrease of the CD56bright natural killer cell-fraction in the lymphocyte subset in the CSF (Fig. 2). Reference values had been previously collected from 29 patients (female: 58%, mean age: 24.1y + − 5.0 standard deviation (SD)) with psychsosomatic disorder (exclusion of inflammatory CNS disorder; CSF: less than 5 cells/μl, normal protein, no intrathecal antibody synthesis).
Fig. 2 Flow Cytometry on day 11 after intoxication. Red dots indicating values of the patients, boxplot based on 29 patients with somatoform disorder (mean and 2 SD). 1: Gated cerebral spinal fluid (CSF) results. 2: Gated peripheral blood (BP) results. 3: Total CSF results. 4: Gated CSF results
With improved walking and hearing but considerable neurocognitive impairment we discharged the patient after 13 days to subsequent rehabilitation.
A neuropsychological assessment on day 18 revealed mild-to-moderate overall cognitive impairments when compared with normative data stratified for age and education (Fig. 3, Supplementary Table S1 for raw scores). Particularly tests assessing cognitive processing speed (e.g., TAP, SDMT, TMT, Time to copy a complex figure) showed consistent alterations from the norm. Learning efficiency of both verbal (RAVLT) and visual material (BVMT-R) was also impaired whereas recall from memory was only reduced for verbal but preserved for complex visual material. Interestingly, the patient showed preserved performance in tests for complex attention and higher executive functions such as planning abilities (D-KEFS Tower Test).
Fig. 3 Results of the neuropsychological assessment on day 18 after intoxication. Test parameters are depicted as z-scores stratified for age and education. Negative values indicate worse performance compared to the normative sample. Performances within the dotted area are within 1 SD from the mean of the normative sample (z = 0 +/− 1). Test parameters are grouped into broader cognitive domains (in bold and italics). Mild-to-moderate deficits in tests for cognitive processing speed, verbal learning and memory as well as efficiency of visual learning were observed. MoCA = Montreal Cognitive Assessment; RAVLT = Rey Auditory Verbal Learning Test; BVMT-R = Brief Visual Memory Test Revised; RCFT = Rey Complex Figure Test; SDMT = Symbol Digit Modalities Test; TMT = Trail Making Test (Part A and B); TAP = Test for Attentional Performance; D-KEFS=Delis-Kaplan Executive Functions System
Discussion and conclusions
Here we report a case of intravenous methadone-induced CNS damage that is unusually bi-phasic in presentation when compared to the available literature. The initial stage was characterized by acute-onset focal neurological signs and localized signs of diffuse CNS toxicity including ischemic changes in MRI while the second stage showed a gradual progression of more widespread damage and cognitive deficits with signs of local immune activation. We thus speculate that the initial damage may have triggered secondary intrathecal inflammation.
Compared to previous case reports, which described oral consumption of methadone ranging from 1,28 mg/L [6] to 0,21 mg/L [7], the present patient consumed methadone at a considerably higher dose. This could explain why acute onset neurological changes have been rarely described while delayed onset of methadone-induced encephalopathy is well known [3]. Our patient also consumed methadone not orally but intravenously. Previous reports describe oral ingestion of methadone or oral or inhaled heroine leading to symmetrical leukoencephalopathy [8, 9]. We detected multifocal edema in the basal ganglia, capsula interna and both cerebellar hemispheres which may reflect direct toxicity of the drug or ischemic changes. Interestingly, the affected areas of the brain show highest expression of mu-opioid receptors and therefore potentially high susceptibility to opioid overstimulation [4]. In addition, the described pattern of the lesions showing restricted diffusion, no contrast enhancement and additional affection of deep gray nuclei and corpus callosum have been linked to toxic and metabolic disorders [10] and go beyond the typical presentation of acute toxic leukoencephalopathy [11]. Considering the possible differential diagnosis for toxic or metabolic disorders (e.g. carbon monoxide (CO), hepatic/hyperammonemic encephalopathy, hypoxic-ischemic encephalopathy (HIE), osmotic demyelination syndrome (extra-pontine myelinolysis) and the clinical features and history of the patient, methadone/opiate-induced encephalopathy along with hypoxic-ischemic encephalopathy are the two most probable causes for the described injury.
As the intravenous methadone consumption was only performed at a single point of time, one would expect a decrease in symptoms correlating with the damage seen in radiological imaging as well as CSF. Controversially, this case shows an improvement of clinical findings yet new lesions in the crura cerebri along with a shift in monocyte subtypes and a decrease in the CD56bright NK-cell-fraction in the control exams at day 11. Other cases confirm this clinical course of improved symptoms along with the increasing extent of reduced diffusion imaging after opiate-consumption [11]. However, even though others previously showed a correlation between opiate-related acute toxic leukoencephalopathy and elevation of CSF myelin basic protein suggesting myelin damage [12], the current case report may be the first to present a CSF leukocyte analysis suggesting a secondary inflammatory process.
Our hypothesis of a secondary inflammatory damage is based on surprisingly specific abnormalities in CSF cell composition characterized by a shift of monocytes from classical (CD14 + CD16-) to non-classical (CD14 + CD16+) and shift from CD56bright non killer (NK) cells to CD56dim NK cells. Notably, both CD14 + CD16 + -monocytes and CD56dim NK cells are known pro-inflammatory cell types which may play a role in the delayed encephalopathy [13, 14]. To further support the hypothesis of secondary inflammatory damage against delayed toxic effects one could take a determination of myelin basic protein into consideration, as it has been shown that myelin basic protein can be elevated in acute toxic leukoencephalopathy [12].
We observed persistent neurocognitive impairments at day 18, especially in tests for cognitive processing speed, verbal and visual learning capacity as well as verbal memory recall. This pattern is in line with previous studies reporting a positive association of larger cognitive impairment with higher methadone doses (for a review see [5]). Associations between domain-specific cognitive impairments and local of brain lesions are however highly variable in young patients due to their usually high levels of cognitive reserve and related compensatory mechanisms [15].
In summary, intravenous methadone intoxication may lead to both primary metabolic-toxic as well as diffuse CNS toxicity that could be interpreted as secondary delayed and potentially inflammatory encephalopathy with persistent neurological deficits including neurocognitive impairment.
Supplementary Information
Additional file 1: Supplementary Figure 1. Additional MRI imaging on day 1 and day 11. Timepoint 1 (Day 1 after intoxication): A: DWI sequence above the latter ventricle; B: FLAIR sequence above the latter ventricle Timepoint 2 (Day 11 after intoxication) FLAIR sequences: C: DWI sequence above the latter ventricle; D: FLAIR sequence above the latter ventricle.
Additional file 2: Supplementary Table S1. Raw Scores and z-scores of neuropsychological test results.
Abbreviations
ADCApparent diffusion coefficient
BVMT-RBrief visuospatial memory test-revised
CDCluster of differentiation
CNSCentral nervous system
CSFCerebrospinal fluid
dBDecibel
D-KEFSDelis-Kaplan executive function test
ECGElectrocardiogram
EEGElectroencephalogram
FACSFluorescence-activated cell scanning
FASTFocused assessment with sonography for trauma
FLAIRFluid attenuated inversion recovery
MRIMagnetic resonance imaging
NKNon killer
RAVLTRey auditory verbal learning test
SDStandard deviation
SDMTSymbol digit modalities test
TAPTest of attentional performance
TMTTrail marking test
TOFTime-of-flight
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jonathan Repple and Svea Haessner are first authors.
Acknowledgements
Not applicable.
Authors’ contributions
JR and SEH analyzed and interpreted the patient data and contributed majorly in writing the manuscript. GMzH supervised the data analysis as well as the writing progress and gave guidance. MP contributed to the manuscript. ASM performed the flow cytometric analysis and contributed to the manuscript. NCL executed the neuropsychological examination and joined with AJ to generate the extended neurocognitive evaluation and graphs. AJ also contributed in writing the neuropsychological part of the manuscript. HW contributed significantly to the manuscript. The author(s) read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editors-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33618681 | 18,992,539 | 2021-02-22 |
What was the dosage of drug 'METHADONE HYDROCHLORIDE'? | Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments.
BACKGROUND
The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone-use and -abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare.
METHODS
Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid.
CONCLUSIONS
This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Background
The mu-opioid agonist methadone is administered orally and is widely used in opioid detoxification and maintenance programs and in the treatment of moderate-to-severe pain in some countries. Oral methadone–use and –abuse have been associated with potential inflammatory and toxic central nervous system (CNS) adverse effects such as cerebellitis [1] and delayed-onset toxic leukoencephalopathy [2–4]. Moreover, cognitive deficits have been reported in long-term methadone users [5]. However, case reports of intravenous methadone application [6] are rare and limited to ischemic changes or hypoxia-induced encephalopathy.
Here, we report a 19-year old male patient who subsequently to recreational intravenous methadone-abuse initially presented with acute neurological deficits with magnetic resonance imaging changes in the bilateral basal ganglia and the cerebellum. Subsequently, the patient developed wide-spread white matter T2-hyperintense lesions and delayed-onset encephalopathy accompanied by signs of secondary inflammation. Cerebral spinal fluid (CSF) flow cytometry revealed an inversion of monocyte and natural killer cell subsets while extensive neuropsychological examination demonstrated persistent cognitive deficits. This suggests a potential sequential toxic and secondary inflammatory CNS damage induced by intravenous methadone.
Case presentation
A 19-year old Caucasian male presented to the University Hospital of Muenster emergency department after being unresponsive for 5 h. After consuming liquid methadone intravenously the night before, the patient awoke and immediately complained of partial bilateral hearing loss, walking impairment and numbness of both inner thighs.
According to third-party history obtained from two accompanying friends (the patient was amnestic regarding the night before) the patient had consumed 3 × 2.5 mL of liquid methadone (produced for substitution therapy) intravenously. They reported observing unconsciousness, urinary incontinence, and a twist of his eyes. The patient and accompanying friends admitted to occasionally orally using illegally obtained methadone and cannabis but credibly denied consuming these substances or other opiods and illegal drugs in the days before. This was the first event of intravenous methadone abuse. The medical history of the patient was otherwise unremarkable.
In the neurological examination the patient presented fluctuating consciousness, severe psychomotor and cognitive slowing (slowed speech, increased response latency, concentration deficits), mild paraparesis of the lower limbs, clonus when testing the left patellar reflex and symmetrical bilateral hypoesthesia of the inner thigh. Medical examination showed a heart rate of 76 beats per minute, blood pressure 121/73 mmHg, peripheral oxygen saturation of 97% and temperature of 36.8 °C. An electrocardiogram (ECG) showed only unspecific change of the ST-segment in V2 and V3. FAST-ultrasound did not reveal any abnormalities.
Blood tests revealed a slightly elevated c-reactive protein (5.2 mg/dl; reference < .5 mg/dl), an elevated GOP (400 U /l; reference: < 30 U/l), GPT (118 U/l; reference < 40 U /l) and an increased creatin-kinase (7104 U/l; reference: < 174 U/l) and lactatdehydrogenase (563 U/l; reference 117–217 U/l). Sodium and potassium levels were within normal range. Intoxication screening of the urine was positive for methadone (2.55 mg/l) and cannabinoids (THC-COOH: 29 μg/l) but was negative for other drugs including non-methadone opioids and barbiturates, benzodiazepines, tricyclic antidepressive drugs, methamphetamines, cocaine, phencyclidine and paracetamol. An initial magnetic resonance imaging (MRI) showed multifocal, bilateral edema of the basal ganglia (Fig. 1a), of both cerebellar hemispheres (Fig. 1b) as well as the capsula interna (Fig. 1c) with diffusion restriction and apparent diffusion coefficient (ADC) signal reductions and fluid attenuated inversion recovery (FLAIR) imaging revealed hyperintense alterations in those areas. In addition, DWI and FLAIR imaging presented mild, confluent white matter abnormalities above the lateral ventricle (Supplementary figure 1A, B). A time-of-flight (TOF)-angiography was normal. An initial spinal tap and subsequent cerebrospinal fluid analysis revealed a disturbance of the blood-brain barrier but normal total protein (542 mg/l) and normal lymphocyte counts (4/μL) and no intrathecal antibody synthesis. An electroencephalogram (EEG) revealed intermittent deceleration without epileptic discharges.
Fig. 1 MRI imaging on day 1 and day 11 after intoxication. Timepoint 1 (Day 1 after intoxication) DWI sequences: a 1 basal ganglia lesions; b Bilateral cerebellar lesions; c Capsula interna lesions, posterior limb. Timepoint 2 (Day 11 after intoxication) FLAIR sequences: d new lesion at timepoint 2 in crura cerebri; e cerebellar lesions; f Capsula interna lesions, posterior limb
After admission, the patient was continuously awake and responsive and did not require intensive care treatment. Initially, walking was impaired without a need for a walking aid.
A transesophageal echocardiography revealed no cardiac abnormalities and especially no endocarditis. Repeated blood cultures were negative. Ear-nose-throat consultation revealed an injury of the inner ear with a diminished ability to hear below 55 dB. We performed treatment with prednisolone for 3 days (days 7–9) at 1 mg per kilogram body weight, which did not cause any immediate conceivable improvement of hearing but the hearing ability improved continuously. The unsteady gait improved to an almost normal level between days 9–11 of inpatient treatment. In contrast, cognitive deficits remained unchanged with increased response latency, slowed speech and concentration deficits. Additionally, the hypoesthesia of the inner thigh remained unchanged.
An additional MRI after 11 days revealed the known FLAIR-hyperintense lesions of basal ganglia, capsula interna (Fig. 1f) and subtle abnormalities above the lateral ventricles (Supplementary figure 1C, D) as well as the cerebellar hemispheres (Fig. 1e), which were now ADC increased. Interestingly, new lesions were found in the crura cerebri bilaterally (Fig. 1d). Another spinal tap revealed an increase of lymphocytes (11/μl), but otherwise no pathological findings with a normal blood-brain barrier. Flow cytometry analysis of cerebrospinal fluid (CSF) cells revealed a shift in monocyte subtypes with a significant increase of the non-classical CD14 + CD16+ monocyte-fraction and decrease of the CD56bright natural killer cell-fraction in the lymphocyte subset in the CSF (Fig. 2). Reference values had been previously collected from 29 patients (female: 58%, mean age: 24.1y + − 5.0 standard deviation (SD)) with psychsosomatic disorder (exclusion of inflammatory CNS disorder; CSF: less than 5 cells/μl, normal protein, no intrathecal antibody synthesis).
Fig. 2 Flow Cytometry on day 11 after intoxication. Red dots indicating values of the patients, boxplot based on 29 patients with somatoform disorder (mean and 2 SD). 1: Gated cerebral spinal fluid (CSF) results. 2: Gated peripheral blood (BP) results. 3: Total CSF results. 4: Gated CSF results
With improved walking and hearing but considerable neurocognitive impairment we discharged the patient after 13 days to subsequent rehabilitation.
A neuropsychological assessment on day 18 revealed mild-to-moderate overall cognitive impairments when compared with normative data stratified for age and education (Fig. 3, Supplementary Table S1 for raw scores). Particularly tests assessing cognitive processing speed (e.g., TAP, SDMT, TMT, Time to copy a complex figure) showed consistent alterations from the norm. Learning efficiency of both verbal (RAVLT) and visual material (BVMT-R) was also impaired whereas recall from memory was only reduced for verbal but preserved for complex visual material. Interestingly, the patient showed preserved performance in tests for complex attention and higher executive functions such as planning abilities (D-KEFS Tower Test).
Fig. 3 Results of the neuropsychological assessment on day 18 after intoxication. Test parameters are depicted as z-scores stratified for age and education. Negative values indicate worse performance compared to the normative sample. Performances within the dotted area are within 1 SD from the mean of the normative sample (z = 0 +/− 1). Test parameters are grouped into broader cognitive domains (in bold and italics). Mild-to-moderate deficits in tests for cognitive processing speed, verbal learning and memory as well as efficiency of visual learning were observed. MoCA = Montreal Cognitive Assessment; RAVLT = Rey Auditory Verbal Learning Test; BVMT-R = Brief Visual Memory Test Revised; RCFT = Rey Complex Figure Test; SDMT = Symbol Digit Modalities Test; TMT = Trail Making Test (Part A and B); TAP = Test for Attentional Performance; D-KEFS=Delis-Kaplan Executive Functions System
Discussion and conclusions
Here we report a case of intravenous methadone-induced CNS damage that is unusually bi-phasic in presentation when compared to the available literature. The initial stage was characterized by acute-onset focal neurological signs and localized signs of diffuse CNS toxicity including ischemic changes in MRI while the second stage showed a gradual progression of more widespread damage and cognitive deficits with signs of local immune activation. We thus speculate that the initial damage may have triggered secondary intrathecal inflammation.
Compared to previous case reports, which described oral consumption of methadone ranging from 1,28 mg/L [6] to 0,21 mg/L [7], the present patient consumed methadone at a considerably higher dose. This could explain why acute onset neurological changes have been rarely described while delayed onset of methadone-induced encephalopathy is well known [3]. Our patient also consumed methadone not orally but intravenously. Previous reports describe oral ingestion of methadone or oral or inhaled heroine leading to symmetrical leukoencephalopathy [8, 9]. We detected multifocal edema in the basal ganglia, capsula interna and both cerebellar hemispheres which may reflect direct toxicity of the drug or ischemic changes. Interestingly, the affected areas of the brain show highest expression of mu-opioid receptors and therefore potentially high susceptibility to opioid overstimulation [4]. In addition, the described pattern of the lesions showing restricted diffusion, no contrast enhancement and additional affection of deep gray nuclei and corpus callosum have been linked to toxic and metabolic disorders [10] and go beyond the typical presentation of acute toxic leukoencephalopathy [11]. Considering the possible differential diagnosis for toxic or metabolic disorders (e.g. carbon monoxide (CO), hepatic/hyperammonemic encephalopathy, hypoxic-ischemic encephalopathy (HIE), osmotic demyelination syndrome (extra-pontine myelinolysis) and the clinical features and history of the patient, methadone/opiate-induced encephalopathy along with hypoxic-ischemic encephalopathy are the two most probable causes for the described injury.
As the intravenous methadone consumption was only performed at a single point of time, one would expect a decrease in symptoms correlating with the damage seen in radiological imaging as well as CSF. Controversially, this case shows an improvement of clinical findings yet new lesions in the crura cerebri along with a shift in monocyte subtypes and a decrease in the CD56bright NK-cell-fraction in the control exams at day 11. Other cases confirm this clinical course of improved symptoms along with the increasing extent of reduced diffusion imaging after opiate-consumption [11]. However, even though others previously showed a correlation between opiate-related acute toxic leukoencephalopathy and elevation of CSF myelin basic protein suggesting myelin damage [12], the current case report may be the first to present a CSF leukocyte analysis suggesting a secondary inflammatory process.
Our hypothesis of a secondary inflammatory damage is based on surprisingly specific abnormalities in CSF cell composition characterized by a shift of monocytes from classical (CD14 + CD16-) to non-classical (CD14 + CD16+) and shift from CD56bright non killer (NK) cells to CD56dim NK cells. Notably, both CD14 + CD16 + -monocytes and CD56dim NK cells are known pro-inflammatory cell types which may play a role in the delayed encephalopathy [13, 14]. To further support the hypothesis of secondary inflammatory damage against delayed toxic effects one could take a determination of myelin basic protein into consideration, as it has been shown that myelin basic protein can be elevated in acute toxic leukoencephalopathy [12].
We observed persistent neurocognitive impairments at day 18, especially in tests for cognitive processing speed, verbal and visual learning capacity as well as verbal memory recall. This pattern is in line with previous studies reporting a positive association of larger cognitive impairment with higher methadone doses (for a review see [5]). Associations between domain-specific cognitive impairments and local of brain lesions are however highly variable in young patients due to their usually high levels of cognitive reserve and related compensatory mechanisms [15].
In summary, intravenous methadone intoxication may lead to both primary metabolic-toxic as well as diffuse CNS toxicity that could be interpreted as secondary delayed and potentially inflammatory encephalopathy with persistent neurological deficits including neurocognitive impairment.
Supplementary Information
Additional file 1: Supplementary Figure 1. Additional MRI imaging on day 1 and day 11. Timepoint 1 (Day 1 after intoxication): A: DWI sequence above the latter ventricle; B: FLAIR sequence above the latter ventricle Timepoint 2 (Day 11 after intoxication) FLAIR sequences: C: DWI sequence above the latter ventricle; D: FLAIR sequence above the latter ventricle.
Additional file 2: Supplementary Table S1. Raw Scores and z-scores of neuropsychological test results.
Abbreviations
ADCApparent diffusion coefficient
BVMT-RBrief visuospatial memory test-revised
CDCluster of differentiation
CNSCentral nervous system
CSFCerebrospinal fluid
dBDecibel
D-KEFSDelis-Kaplan executive function test
ECGElectrocardiogram
EEGElectroencephalogram
FACSFluorescence-activated cell scanning
FASTFocused assessment with sonography for trauma
FLAIRFluid attenuated inversion recovery
MRIMagnetic resonance imaging
NKNon killer
RAVLTRey auditory verbal learning test
SDStandard deviation
SDMTSymbol digit modalities test
TAPTest of attentional performance
TMTTrail marking test
TOFTime-of-flight
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jonathan Repple and Svea Haessner are first authors.
Acknowledgements
Not applicable.
Authors’ contributions
JR and SEH analyzed and interpreted the patient data and contributed majorly in writing the manuscript. GMzH supervised the data analysis as well as the writing progress and gave guidance. MP contributed to the manuscript. ASM performed the flow cytometric analysis and contributed to the manuscript. NCL executed the neuropsychological examination and joined with AJ to generate the extended neurocognitive evaluation and graphs. AJ also contributed in writing the neuropsychological part of the manuscript. HW contributed significantly to the manuscript. The author(s) read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editors-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | 3 ? 2.5 ML (LIQUID METHADONE) | DrugDosageText | CC BY | 33618681 | 18,992,539 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abortion induced'. | Valproate use in women aged 15-44 years: an observational study in general practice.
BACKGROUND
Valproate is a known teratogen. In April 2018, the Medicines and Healthcare products Regulatory Agency (MHRA) restricted its use in women and banned use in pregnancy, except for epilepsy with no other effective treatment. To date, there is limited information on valproate prescribing within primary care.
OBJECTIVE
To characterise valproate prescribing to women of childbearing age, recorded advice or GP prescribed contraception, and recorded pregnancies.
METHODS
A cross-sectional study of patients from all 141 general practices across three clinical commissioning groups (CCGs) in East London.
METHODS
Women aged 15-44 years prescribed valproate between 1 October 2017 and 1 January 2020 were included. Exclusion criteria were early menopause, sterilisation procedures, or hysterectomy. Pseudonymised data on valproate indication, pregnancy, pre-conception, and contraception advice were retrospectively extracted from general practice consultation data. Data were analysed by quarter using univariate statistics.
RESULTS
Of the total 1 042 463 registered patients, 344 women aged 15-44 years were prescribed valproate during the study period; 14 were excluded. There were 10 pregnancies during possible valproate exposure; one was terminated. During the study period, the number of women prescribed valproate significantly decreased (P = 0.003). The pregnancy rate decreased from 9.9/1000 on valproate before the MHRA April 2018 warning, to an average of 2.8/1000 afterwards. Recorded pre-conception and contraception advice increased by 79%, from 24% to 43%, of women prescribed valproate.
CONCLUSIONS
With continued pregnancies in women aged 15-44 years prescribed valproate, patient education and foetal outcomes remain ongoing concerns. Further improvements are needed to ensure women make informed reproductive choices and safeguard future pregnancies from valproate exposure.
How this fits in
Valproate is a known teratogen causing physical abnormalities and is also associated with neurodevelopmental delay, including autism. Recent MHRA guidance restricts the use of valproate in women with reproductive potential. This study shows an increase in patient valproate education and a reduction in valproate prescribing, but ongoing pregnancies within this group highlight continuing concerns about valproate exposure in pregnancy. A need to improve delivery of high quality patient education is demonstrated to enable women to make informed reproductive choices and safeguard future pregnancies against valproate exposure.
Introduction
Valproate is an antiepileptic drug (AED) and mood stabiliser licensed in the UK for use in the treatment of all forms of epilepsy, mania in bipolar affective disorder, and migraine prophylaxis.1 Valproate is a known teratogen. The risks of valproate use in pregnancy are well documented with wide-ranging effects of in utero valproate exposure, including congenital malformations and neurodevelopmental delay.2,3
Of the AEDs, valproate has been consistently highlighted as having the highest rate of congenital malformations.2,4 Based on two major meta-analyses of data from studies worldwide, the rate of major congenital malformations in babies born to mothers taking valproate monotherapy during pregnancy has been estimated to be 11% compared with 3% in women without epilepsy.2,3
Beyond birth, there is consistent evidence that valproate use during pregnancy is associated with persistently impaired neurodevelopment, which affects 30%–40% of children exposed to valproate during this time.4–7 The effects are varied and include four times increased risk of psychomotor delay, seven times increased risk of cognitive development delay, and eight times increased risk of language delay.8 There are strong associations with the development of autism where risk is estimated to be increased up to 17 times.3,8 In utero valproate exposure is also associated with a significant decrease in intelligent quotient (IQ) of around 8 IQ points.3 This reduction in IQ alone is likely sufficient to affect education and lifelong occupation.3 Most congenital birth defects and neurodevelopmental complications arising from in utero valproate use will have a lifetime financial, medical, and social care burden for affected families and the state.9
In response to the accumulating body of evidence of valproate risk, as well as pressure from patient advocate groups, there have been several stepwise changes in public policy and clinical guidelines. In the UK, the MHRA issued a press release in April 2018 restricting the use of valproate in women of childbearing potential unless they are on a pregnancy prevention programme.10 The pregnancy prevention programme aims to enable women and their clinicians to make informed decisions about their care by providing information about the risks of pregnancy and providing highly effective contraception, including long-acting reversible contraception (LARC) methods such as intrauterine devices and the progesterone-only implant.11 Overall trends since then suggest a substantial reduction in valproate prescriptions in women of childbearing age,12 but little is known about the extent to which the 2018 MHRA guidance has been implemented.
This study aimed to characterise: valproate prescribing to women of childbearing age, recorded advice or contraception prescribed by GPs, and recorded pregnancies between 2017 and 2020 across three CCG areas of East London.
Method
This cross-sectional study included de-identified general practice data from all 141 GP practices in three adjacent inner-urban CCGs in East London (City and Hackney, Tower Hamlets, and Newham) between 1 October 2017 and 1 January 2020. These CCG areas are among the most ethnically diverse and deprived in both London and the UK. These GP practices all use EMIS Web (Egton Medical Information Systems) as an electronic health record to document patient interactions and prescribing. De-identified patient data for the relevant study items were centrally extracted and securely stored by the Clinical Effectiveness Group (CEG), Queen Mary University of London. The types of data accessed by the CEG and the information sharing role of the CEG has been described elsewhere.13
De-identified data were retrospectively extracted for the start of each quarter between 1 October 2017 and 1 January 2020 to cover the 6 months before the release of the MHRA guidance in April 2018 and the time until this study (that is, until data extraction). The cohort were women aged 15–44 years currently registered at the 141 practices who were prescribed valproate in the past 3 months, before the relevant start date in the quarter. Valproate prescriptions included all generic preparations of valproate, sodium valproate, semisodium valproate, and all brand names available in the UK (Epilim Chrono, Epival, Depakote, Episenta, and Convulex). Patients were excluded if they had previously undergone early menopause, sterilisation procedures, or hysterectomy. Pregnancy was inferred through an algorithm combininga number of Read codes related to pregnancy and used in the national immunisation pregnancy codeset.14 Data extraction took place in February 2020; the database was not updated during this time.
Read codes of interest were identified relating to inclusion (women aged 15–44 years prescribed valproate) and exclusion criteria (early menopause, sterilisation, and hysterectomy), pre-conception advice, contraception advice, provided or prescribed contraception, and long-term problems as the likely indication for valproate prescription (See Supplementary Table S1).
Data for these Read codes were extracted for specific timeframes, relative to the Read code date of the valproate prescription, within the quarter (see Supplementary Table S1). Duplicates were removed with the first occurrence being used for analysis. All data were analysed using R (version 3.6.2), including linear regression to compare outcomes and assess statistical significance. Missing data were interpreted as that outcome not being true for that patient at that time, as recorded by the GP. All patients were assigned a pseudonymised identifier as part of the extraction process. This work was conducted according to STROBE guidelines on reporting observational studies.15
Results
Quarterly data were extracted between 1 October 2017 and 1 January 2020 for the three CCG areas with a total of 1 042 463 registered patients in 2018 (City and Hackney, n = 318 637; Newham, n = 398 907; and Tower Hamlets, n = 324 919). There were a total of 344 women aged 15–44 years prescribed valproate, of whom 14 patients were excluded (early menopause, n = 1; sterilisation procedures, n = 10; or hysterectomy, n = 3) to give a final sample size of 330. The median age of the sample was 34 years (interquartile range 27–41 years) (Table 1). The ethnic group of the sample was predominantly White followed by South Asian.
Table 1. Demographic characteristics of 330 women aged 15–44 years prescribed sodium valproate between 1 October 2017 and 1 January 2020 in East London
Age, yearsa n (%)
15–19 38 (12)
20–24 22 (7)
25–29 54 (16)
30–34 69 (21)
35–39 60 (18)
≥40 87 (26)
Ethnic group a
White 150 (45)
Black 49 (15)
South Asian 87 (26)
Other 22 (7)
Unknown 22 (7)
Received pre-conception or contraception advice b 151 (46)
Prescribed contraception b 90 (27)
Prescribed LARCc 48 (53)
Prescribed non-LARCc 42 (47)
Received advice or contraception b 191 (58)
aData relate to most recent record for age and ethnic group. bAt least once during study period. cLong-acting reversible contraception (LARC): copper intrauterine device, levonorgestrel 13.5 mg/19.5 mg/52 mg intrauterine system, and progestogen-only implant. Non-LARC contraception: combined hormonal contraception including combined contraceptive pill, transdermal patch and vaginal ring, progestogen-only pill, progestogen-only injectable depot medroxyprogesterone acetate, condoms, and diaphragms.
Of the total 330 unique individuals, 63 were prescribed valproate at every quarterly time point in the study period. Over this time, the total number of women prescribed valproate decreased by 36% from 214 in October 2017 to 136 in January 2020 (Figure 1). This decrease in valproate prescribing before and after the MHRA warning in April 2018 was statistically significant (P = 0.003).
Figure 1. Number of women prescribed valproate between 2017 and 2020 in East London
In total, there were 10 pregnancies in nine women prescribed valproate during the study period, one of which was terminated (Table 2). The pregnancy rate (defined as the number of pregnancies in the year divided by the number of women on valproate x 1000) averaged 9.9/1000 in the three quarters before the MHRA announcement in April 2018 to an average of 2.8/1000 in the quarters after April 2018, which was a decrease of 71%. (Table 2). The median age of these women was 30 years (interquartile range 28–32 years). Of these women, 89% (n = 9) were recorded as having epilepsy, 22% (n = 2) were recorded as having bipolar affective disorder, and 11% (n = 1) were on the learning disability register. In terms of ethnic group, 40% (n = 4) of these women were in White and 50% (n = 5) were in Black, South Asian, and Other ethnic groups (missing data n = 1). Two of these women were recorded as having received pre-conception advice; however, only one of these was before the recorded pregnancy. Four of these women were recorded as having received contraception advice; this was recorded on two occasions before pregnancy (data not shown).
Table 2. Pregnancy and pregnancy rates by quarter between 1 October 2017 and 1 January 2020 in East London
Quarter
10/17 01/18 04/18 07/18 10/18 01/19 04/19 07/19 10/19 01/20
Total, n 214 198 194 179 178 162 148 143 142 136
Pregnancies, n a 4 1 1 0 0 1 0 1 0 1
Pregnancy rate (average per 1000 population) 9.9 2.8
aNew pregnancies in this quarter; corrected for one termination or miscarriage.
Indications for valproate for these 330 individuals is shown in Table 3. The most common indication for women prescribed valproate, at both the start and end of the study period, was epilepsy (65%; n = 139 and n = 88, respectively) followed by bipolar disorder (14% and 15%; n = 31 and n = 20, respectively). The distribution of indications was largely unchanged at the end of the study period despite an overall reduction in the number of women prescribed valproate.
Table 3. Indication for valproate for women included in the first and last quarters of the study period
Valproateindicationa Dataextraction from 1 Oct 2017 Data extraction from 1 Jan 2020
n (%) n (%)
Epilepsy 139 (65) 88 (65)
Bipolar disorder 31 (14) 20 (15)
Migraine 4 (2) 2 (1)
Learning difficulties 5 (2) 5 (4)
Other or unknown 35 (16) 21 (15)
Total patients 214 (100) 136 (100)
aLikely indication inferred from recorded long-term conditions on electronic health record.
The proportion of women prescribed valproate receiving pre-conception advice or advice on contraception increased by 79% during the study period from 24% (n = 52/214 women) to 43% (n = 58/136 women) (Figure 2). Recorded contraception prescribing rates stayed approximately constant at around 20%. At the beginning of the study period, 39% of women (n = 84/214) prescribed valproate were given advice and/or contraception, which had increased to 49% (n = 66/136) by the end of the study period.
Figure 2. Change in pre-conception or contraception advice (purple), prescribed contraception (blue), and women receiving advice and/or contraception (orange), normalised to the number of women prescribed valproate
Discussion
Summary
Ten pregnancies potentially exposed to valproate were identified between October 2017 and January 2020 in East London. Pre-conception or contraception advice was poorly recorded in the general practice record system before these pregnancies, with only one woman with pre-conception advice and two women with contraception or contraceptive advice recorded. This may be owing to a failure of appropriate counselling or a failure to record such information, or both. Such failures may limit the ability of women to make informed decisions about their treatment with valproate and about family planning.
Over the study period, there was an overall improvement in the recording of pre-conception and contraception advice to women of childbearing age prescribed valproate, which was in association with a 71% decrease in pregnancy rate in women of childbearing age prescribed valproate. This suggests the MHRA 2018 recommendations led to increased levels of recording and/or patient education, with more women making informed decisions about their ongoing care in relation to valproate use and pregnancy.
There was a statistically significant decrease in the number of women prescribed valproate before, compared with after the April 2018 MHRA warning. This decrease was most pronounced in the year following the MHRA announcement. However, the decline has slowed since then and a valproate prescription in general practice continues to pose substantial risks to pregnancies in these women.
The MHRA guidance bans the use of valproate for women during pregnancy for psychiatric and all other indications except for epilepsy if it is the only option, and restricts its use more generally unless combined with effective contraception and a pregnancy prevention plan.10 The majority of the 10 at-risk pregnancies identified were in women with epilepsy, which may reflect that there was no alternative treatment. However, despite an overall reduction in the number of women prescribed valproate, the proportion of women prescribed valproate for indications other than epilepsy remained largely unchanged between the start and end of the study period; for example, a number of women were still prescribed valproate for bipolar affective disorder or learning disabilities where alternative treatments were more appropriate. Changing prescribing for these women will reduce the risk of further valproate-exposed pregnancies.
Strengths and limitations
These data are from a large number of urban GP practices that are located in areas of high ethnic diversity and deprivation, which are factors well documented to contribute to health inequalities.16 However, contraceptive and pre-pregnancy advice are activities undertaken by all GPs and there is no reason to assume that those in the study locality differed in their advice and prescription from any other area.
Prescribing for long-term conditions is undertaken almost entirely by GPs for whom the electronic health record is an accurate record. However, not all prescribed medication may actually be dispensed or used by the patient, and it is possible that use of prescribed valproate by patients was stopped before or at some time during pregnancy. This study is only able to identify where GPs have recorded that pre-conception and contraception advice was given, so these figures may underestimate the true numbers of women who received such advice from other sources. Some women are likely to have contraception managed by third-party clinics or were using other methods including rhythm methods, condoms or diaphragms, and partner vasectomy. These are all likely to be poorly recorded in a woman’s record but may be more likely to be subsumed in the coding for ‘contraception advice given’.
Current pregnancy was inferred in this study, using codes indicating a current pregnancy, including pregnancy, antenatal care, and a duration of 9 months from the earliest record of pregnancy. It is possible that some women were not pregnant at a time of overlapping valproate prescription. The number of pregnancies in this study was small and a larger scale study with mother and baby linkage is required to assess the effects of valproate on foetal outcomes.
Comparison with existing literature
The authors are not aware of any recent studies of valproate use that have considered contraceptive and pregnancy outcomes in UK general practice since the MHRA warning. Despite the recent input from the MHRA, there have been concerns for many years about a lack of patient education surrounding valproate use in women of childbearing potential.7,10,17 A 2017 survey of women of childbearing potential prescribed valproate for epilepsy conducted by the Epilepsy Action, Epilepsy Society, and Young Epilepsy suggests around 70% of women surveyed had not received information about changes in advice about the pregnancy-associated risk.18 Further to the 2018 MHRA guidance, joint guidelines from the Royal College of General Practitioners and Royal College of Physicians have provided advice to clinicians on how to broach, record, and manage these conversations with women of childbearing age.11 GP recording of the pregnancy prevention programme is in its infancy and there is currently no way to easily electronically access or record the MHRA consent form signed by patient and specialist.
The Neurodevelopmental Effects of Antiepileptic Drugs study indicated that valproate use in pregnancy in the US and UK reduced between 1999 and 2007.19 More recently, primary care data collected between 2010 and 2019 in the UK suggest an overall decline in the initiation of valproate prescription for females aged <45 years.12 In particular, the authors noted an 80% decrease in initiation of valproate in females in the first half of 2019 compared with the first half of 2010. This trend was noted across all indications (epilepsy, bipolar disorder, migraine, and unknown), with epilepsy being the most common indication for valproate use.12 The Cumberlege report published after this study has underlined the substantial risks of valproate prescribing, and the need to improve safety and monitoring of outcomes.20,21
Implications for research and practice
There is currently no standard pathway in the UK for following up babies born to mothers who have taken valproate during pregnancy.11 Given that some neurodevelopmental issues may not arise for several years, in utero medication exposure may be overlooked as a cause. This study has identified nine children that might benefit from follow-up in this locality. At a research level, this could be done through de-identified linkage of primary and secondary care information with an appropriately large sample size. There are also plans to create a valproate register for children of mothers taking valproate during pregnancy.11
For clinicians, this work demonstrates the need to improve patient education for women of childbearing potential prescribed valproate. At a practice level, accurate recording of patient encounters is required to reflect the quality of care that is being provided.
Valproate prescribing to women aged <45 years has significantly decreased since the April 2018 MHRA warning. However, this study shows that despite the MHRA recommendations, valproate prescription, in association with a lack of recorded advice as well as continuing prescription outside of MHRA guidance, may continue to place women and their children at risk of exposure during pregnancy. This demonstrates the need for improved patient education and recording of patient encounters to ensure that women receive high quality care to inform reproductive choices.
Funding
At the time of this work, Samantha Jane Beardsley was a foundation year 2 academic doctor funded by Barts Health NHS Trust. There was no specific funding for this work.
Ethical approval
The extracted data consisted of deidentified routinely acquire patient data derived from general practitioner electronic health records with their permission as data controllers and reported as aggregate data. No ethical committee consent was required for such data uses.
Provenance
Freely submitted; externally peer reviewed.
Acknowledgements
The authors would like to thank Dr Ryan Beardsley for lending his expertise in data manipulation using R. The authors are also grateful to the GPs and their practice teams for allowing use of their patient records and to the Clinical Effectiveness Group for providing coding, advice, and access to these records, and maintenance of a high quality dataset with agreed coding entries.
Competing interests
The authors declare that no competing interests exist. | DIVALPROEX SODIUM | DrugsGivenReaction | CC BY | 33619016 | 19,419,409 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | Valproate use in women aged 15-44 years: an observational study in general practice.
BACKGROUND
Valproate is a known teratogen. In April 2018, the Medicines and Healthcare products Regulatory Agency (MHRA) restricted its use in women and banned use in pregnancy, except for epilepsy with no other effective treatment. To date, there is limited information on valproate prescribing within primary care.
OBJECTIVE
To characterise valproate prescribing to women of childbearing age, recorded advice or GP prescribed contraception, and recorded pregnancies.
METHODS
A cross-sectional study of patients from all 141 general practices across three clinical commissioning groups (CCGs) in East London.
METHODS
Women aged 15-44 years prescribed valproate between 1 October 2017 and 1 January 2020 were included. Exclusion criteria were early menopause, sterilisation procedures, or hysterectomy. Pseudonymised data on valproate indication, pregnancy, pre-conception, and contraception advice were retrospectively extracted from general practice consultation data. Data were analysed by quarter using univariate statistics.
RESULTS
Of the total 1 042 463 registered patients, 344 women aged 15-44 years were prescribed valproate during the study period; 14 were excluded. There were 10 pregnancies during possible valproate exposure; one was terminated. During the study period, the number of women prescribed valproate significantly decreased (P = 0.003). The pregnancy rate decreased from 9.9/1000 on valproate before the MHRA April 2018 warning, to an average of 2.8/1000 afterwards. Recorded pre-conception and contraception advice increased by 79%, from 24% to 43%, of women prescribed valproate.
CONCLUSIONS
With continued pregnancies in women aged 15-44 years prescribed valproate, patient education and foetal outcomes remain ongoing concerns. Further improvements are needed to ensure women make informed reproductive choices and safeguard future pregnancies from valproate exposure.
How this fits in
Valproate is a known teratogen causing physical abnormalities and is also associated with neurodevelopmental delay, including autism. Recent MHRA guidance restricts the use of valproate in women with reproductive potential. This study shows an increase in patient valproate education and a reduction in valproate prescribing, but ongoing pregnancies within this group highlight continuing concerns about valproate exposure in pregnancy. A need to improve delivery of high quality patient education is demonstrated to enable women to make informed reproductive choices and safeguard future pregnancies against valproate exposure.
Introduction
Valproate is an antiepileptic drug (AED) and mood stabiliser licensed in the UK for use in the treatment of all forms of epilepsy, mania in bipolar affective disorder, and migraine prophylaxis.1 Valproate is a known teratogen. The risks of valproate use in pregnancy are well documented with wide-ranging effects of in utero valproate exposure, including congenital malformations and neurodevelopmental delay.2,3
Of the AEDs, valproate has been consistently highlighted as having the highest rate of congenital malformations.2,4 Based on two major meta-analyses of data from studies worldwide, the rate of major congenital malformations in babies born to mothers taking valproate monotherapy during pregnancy has been estimated to be 11% compared with 3% in women without epilepsy.2,3
Beyond birth, there is consistent evidence that valproate use during pregnancy is associated with persistently impaired neurodevelopment, which affects 30%–40% of children exposed to valproate during this time.4–7 The effects are varied and include four times increased risk of psychomotor delay, seven times increased risk of cognitive development delay, and eight times increased risk of language delay.8 There are strong associations with the development of autism where risk is estimated to be increased up to 17 times.3,8 In utero valproate exposure is also associated with a significant decrease in intelligent quotient (IQ) of around 8 IQ points.3 This reduction in IQ alone is likely sufficient to affect education and lifelong occupation.3 Most congenital birth defects and neurodevelopmental complications arising from in utero valproate use will have a lifetime financial, medical, and social care burden for affected families and the state.9
In response to the accumulating body of evidence of valproate risk, as well as pressure from patient advocate groups, there have been several stepwise changes in public policy and clinical guidelines. In the UK, the MHRA issued a press release in April 2018 restricting the use of valproate in women of childbearing potential unless they are on a pregnancy prevention programme.10 The pregnancy prevention programme aims to enable women and their clinicians to make informed decisions about their care by providing information about the risks of pregnancy and providing highly effective contraception, including long-acting reversible contraception (LARC) methods such as intrauterine devices and the progesterone-only implant.11 Overall trends since then suggest a substantial reduction in valproate prescriptions in women of childbearing age,12 but little is known about the extent to which the 2018 MHRA guidance has been implemented.
This study aimed to characterise: valproate prescribing to women of childbearing age, recorded advice or contraception prescribed by GPs, and recorded pregnancies between 2017 and 2020 across three CCG areas of East London.
Method
This cross-sectional study included de-identified general practice data from all 141 GP practices in three adjacent inner-urban CCGs in East London (City and Hackney, Tower Hamlets, and Newham) between 1 October 2017 and 1 January 2020. These CCG areas are among the most ethnically diverse and deprived in both London and the UK. These GP practices all use EMIS Web (Egton Medical Information Systems) as an electronic health record to document patient interactions and prescribing. De-identified patient data for the relevant study items were centrally extracted and securely stored by the Clinical Effectiveness Group (CEG), Queen Mary University of London. The types of data accessed by the CEG and the information sharing role of the CEG has been described elsewhere.13
De-identified data were retrospectively extracted for the start of each quarter between 1 October 2017 and 1 January 2020 to cover the 6 months before the release of the MHRA guidance in April 2018 and the time until this study (that is, until data extraction). The cohort were women aged 15–44 years currently registered at the 141 practices who were prescribed valproate in the past 3 months, before the relevant start date in the quarter. Valproate prescriptions included all generic preparations of valproate, sodium valproate, semisodium valproate, and all brand names available in the UK (Epilim Chrono, Epival, Depakote, Episenta, and Convulex). Patients were excluded if they had previously undergone early menopause, sterilisation procedures, or hysterectomy. Pregnancy was inferred through an algorithm combininga number of Read codes related to pregnancy and used in the national immunisation pregnancy codeset.14 Data extraction took place in February 2020; the database was not updated during this time.
Read codes of interest were identified relating to inclusion (women aged 15–44 years prescribed valproate) and exclusion criteria (early menopause, sterilisation, and hysterectomy), pre-conception advice, contraception advice, provided or prescribed contraception, and long-term problems as the likely indication for valproate prescription (See Supplementary Table S1).
Data for these Read codes were extracted for specific timeframes, relative to the Read code date of the valproate prescription, within the quarter (see Supplementary Table S1). Duplicates were removed with the first occurrence being used for analysis. All data were analysed using R (version 3.6.2), including linear regression to compare outcomes and assess statistical significance. Missing data were interpreted as that outcome not being true for that patient at that time, as recorded by the GP. All patients were assigned a pseudonymised identifier as part of the extraction process. This work was conducted according to STROBE guidelines on reporting observational studies.15
Results
Quarterly data were extracted between 1 October 2017 and 1 January 2020 for the three CCG areas with a total of 1 042 463 registered patients in 2018 (City and Hackney, n = 318 637; Newham, n = 398 907; and Tower Hamlets, n = 324 919). There were a total of 344 women aged 15–44 years prescribed valproate, of whom 14 patients were excluded (early menopause, n = 1; sterilisation procedures, n = 10; or hysterectomy, n = 3) to give a final sample size of 330. The median age of the sample was 34 years (interquartile range 27–41 years) (Table 1). The ethnic group of the sample was predominantly White followed by South Asian.
Table 1. Demographic characteristics of 330 women aged 15–44 years prescribed sodium valproate between 1 October 2017 and 1 January 2020 in East London
Age, yearsa n (%)
15–19 38 (12)
20–24 22 (7)
25–29 54 (16)
30–34 69 (21)
35–39 60 (18)
≥40 87 (26)
Ethnic group a
White 150 (45)
Black 49 (15)
South Asian 87 (26)
Other 22 (7)
Unknown 22 (7)
Received pre-conception or contraception advice b 151 (46)
Prescribed contraception b 90 (27)
Prescribed LARCc 48 (53)
Prescribed non-LARCc 42 (47)
Received advice or contraception b 191 (58)
aData relate to most recent record for age and ethnic group. bAt least once during study period. cLong-acting reversible contraception (LARC): copper intrauterine device, levonorgestrel 13.5 mg/19.5 mg/52 mg intrauterine system, and progestogen-only implant. Non-LARC contraception: combined hormonal contraception including combined contraceptive pill, transdermal patch and vaginal ring, progestogen-only pill, progestogen-only injectable depot medroxyprogesterone acetate, condoms, and diaphragms.
Of the total 330 unique individuals, 63 were prescribed valproate at every quarterly time point in the study period. Over this time, the total number of women prescribed valproate decreased by 36% from 214 in October 2017 to 136 in January 2020 (Figure 1). This decrease in valproate prescribing before and after the MHRA warning in April 2018 was statistically significant (P = 0.003).
Figure 1. Number of women prescribed valproate between 2017 and 2020 in East London
In total, there were 10 pregnancies in nine women prescribed valproate during the study period, one of which was terminated (Table 2). The pregnancy rate (defined as the number of pregnancies in the year divided by the number of women on valproate x 1000) averaged 9.9/1000 in the three quarters before the MHRA announcement in April 2018 to an average of 2.8/1000 in the quarters after April 2018, which was a decrease of 71%. (Table 2). The median age of these women was 30 years (interquartile range 28–32 years). Of these women, 89% (n = 9) were recorded as having epilepsy, 22% (n = 2) were recorded as having bipolar affective disorder, and 11% (n = 1) were on the learning disability register. In terms of ethnic group, 40% (n = 4) of these women were in White and 50% (n = 5) were in Black, South Asian, and Other ethnic groups (missing data n = 1). Two of these women were recorded as having received pre-conception advice; however, only one of these was before the recorded pregnancy. Four of these women were recorded as having received contraception advice; this was recorded on two occasions before pregnancy (data not shown).
Table 2. Pregnancy and pregnancy rates by quarter between 1 October 2017 and 1 January 2020 in East London
Quarter
10/17 01/18 04/18 07/18 10/18 01/19 04/19 07/19 10/19 01/20
Total, n 214 198 194 179 178 162 148 143 142 136
Pregnancies, n a 4 1 1 0 0 1 0 1 0 1
Pregnancy rate (average per 1000 population) 9.9 2.8
aNew pregnancies in this quarter; corrected for one termination or miscarriage.
Indications for valproate for these 330 individuals is shown in Table 3. The most common indication for women prescribed valproate, at both the start and end of the study period, was epilepsy (65%; n = 139 and n = 88, respectively) followed by bipolar disorder (14% and 15%; n = 31 and n = 20, respectively). The distribution of indications was largely unchanged at the end of the study period despite an overall reduction in the number of women prescribed valproate.
Table 3. Indication for valproate for women included in the first and last quarters of the study period
Valproateindicationa Dataextraction from 1 Oct 2017 Data extraction from 1 Jan 2020
n (%) n (%)
Epilepsy 139 (65) 88 (65)
Bipolar disorder 31 (14) 20 (15)
Migraine 4 (2) 2 (1)
Learning difficulties 5 (2) 5 (4)
Other or unknown 35 (16) 21 (15)
Total patients 214 (100) 136 (100)
aLikely indication inferred from recorded long-term conditions on electronic health record.
The proportion of women prescribed valproate receiving pre-conception advice or advice on contraception increased by 79% during the study period from 24% (n = 52/214 women) to 43% (n = 58/136 women) (Figure 2). Recorded contraception prescribing rates stayed approximately constant at around 20%. At the beginning of the study period, 39% of women (n = 84/214) prescribed valproate were given advice and/or contraception, which had increased to 49% (n = 66/136) by the end of the study period.
Figure 2. Change in pre-conception or contraception advice (purple), prescribed contraception (blue), and women receiving advice and/or contraception (orange), normalised to the number of women prescribed valproate
Discussion
Summary
Ten pregnancies potentially exposed to valproate were identified between October 2017 and January 2020 in East London. Pre-conception or contraception advice was poorly recorded in the general practice record system before these pregnancies, with only one woman with pre-conception advice and two women with contraception or contraceptive advice recorded. This may be owing to a failure of appropriate counselling or a failure to record such information, or both. Such failures may limit the ability of women to make informed decisions about their treatment with valproate and about family planning.
Over the study period, there was an overall improvement in the recording of pre-conception and contraception advice to women of childbearing age prescribed valproate, which was in association with a 71% decrease in pregnancy rate in women of childbearing age prescribed valproate. This suggests the MHRA 2018 recommendations led to increased levels of recording and/or patient education, with more women making informed decisions about their ongoing care in relation to valproate use and pregnancy.
There was a statistically significant decrease in the number of women prescribed valproate before, compared with after the April 2018 MHRA warning. This decrease was most pronounced in the year following the MHRA announcement. However, the decline has slowed since then and a valproate prescription in general practice continues to pose substantial risks to pregnancies in these women.
The MHRA guidance bans the use of valproate for women during pregnancy for psychiatric and all other indications except for epilepsy if it is the only option, and restricts its use more generally unless combined with effective contraception and a pregnancy prevention plan.10 The majority of the 10 at-risk pregnancies identified were in women with epilepsy, which may reflect that there was no alternative treatment. However, despite an overall reduction in the number of women prescribed valproate, the proportion of women prescribed valproate for indications other than epilepsy remained largely unchanged between the start and end of the study period; for example, a number of women were still prescribed valproate for bipolar affective disorder or learning disabilities where alternative treatments were more appropriate. Changing prescribing for these women will reduce the risk of further valproate-exposed pregnancies.
Strengths and limitations
These data are from a large number of urban GP practices that are located in areas of high ethnic diversity and deprivation, which are factors well documented to contribute to health inequalities.16 However, contraceptive and pre-pregnancy advice are activities undertaken by all GPs and there is no reason to assume that those in the study locality differed in their advice and prescription from any other area.
Prescribing for long-term conditions is undertaken almost entirely by GPs for whom the electronic health record is an accurate record. However, not all prescribed medication may actually be dispensed or used by the patient, and it is possible that use of prescribed valproate by patients was stopped before or at some time during pregnancy. This study is only able to identify where GPs have recorded that pre-conception and contraception advice was given, so these figures may underestimate the true numbers of women who received such advice from other sources. Some women are likely to have contraception managed by third-party clinics or were using other methods including rhythm methods, condoms or diaphragms, and partner vasectomy. These are all likely to be poorly recorded in a woman’s record but may be more likely to be subsumed in the coding for ‘contraception advice given’.
Current pregnancy was inferred in this study, using codes indicating a current pregnancy, including pregnancy, antenatal care, and a duration of 9 months from the earliest record of pregnancy. It is possible that some women were not pregnant at a time of overlapping valproate prescription. The number of pregnancies in this study was small and a larger scale study with mother and baby linkage is required to assess the effects of valproate on foetal outcomes.
Comparison with existing literature
The authors are not aware of any recent studies of valproate use that have considered contraceptive and pregnancy outcomes in UK general practice since the MHRA warning. Despite the recent input from the MHRA, there have been concerns for many years about a lack of patient education surrounding valproate use in women of childbearing potential.7,10,17 A 2017 survey of women of childbearing potential prescribed valproate for epilepsy conducted by the Epilepsy Action, Epilepsy Society, and Young Epilepsy suggests around 70% of women surveyed had not received information about changes in advice about the pregnancy-associated risk.18 Further to the 2018 MHRA guidance, joint guidelines from the Royal College of General Practitioners and Royal College of Physicians have provided advice to clinicians on how to broach, record, and manage these conversations with women of childbearing age.11 GP recording of the pregnancy prevention programme is in its infancy and there is currently no way to easily electronically access or record the MHRA consent form signed by patient and specialist.
The Neurodevelopmental Effects of Antiepileptic Drugs study indicated that valproate use in pregnancy in the US and UK reduced between 1999 and 2007.19 More recently, primary care data collected between 2010 and 2019 in the UK suggest an overall decline in the initiation of valproate prescription for females aged <45 years.12 In particular, the authors noted an 80% decrease in initiation of valproate in females in the first half of 2019 compared with the first half of 2010. This trend was noted across all indications (epilepsy, bipolar disorder, migraine, and unknown), with epilepsy being the most common indication for valproate use.12 The Cumberlege report published after this study has underlined the substantial risks of valproate prescribing, and the need to improve safety and monitoring of outcomes.20,21
Implications for research and practice
There is currently no standard pathway in the UK for following up babies born to mothers who have taken valproate during pregnancy.11 Given that some neurodevelopmental issues may not arise for several years, in utero medication exposure may be overlooked as a cause. This study has identified nine children that might benefit from follow-up in this locality. At a research level, this could be done through de-identified linkage of primary and secondary care information with an appropriately large sample size. There are also plans to create a valproate register for children of mothers taking valproate during pregnancy.11
For clinicians, this work demonstrates the need to improve patient education for women of childbearing potential prescribed valproate. At a practice level, accurate recording of patient encounters is required to reflect the quality of care that is being provided.
Valproate prescribing to women aged <45 years has significantly decreased since the April 2018 MHRA warning. However, this study shows that despite the MHRA recommendations, valproate prescription, in association with a lack of recorded advice as well as continuing prescription outside of MHRA guidance, may continue to place women and their children at risk of exposure during pregnancy. This demonstrates the need for improved patient education and recording of patient encounters to ensure that women receive high quality care to inform reproductive choices.
Funding
At the time of this work, Samantha Jane Beardsley was a foundation year 2 academic doctor funded by Barts Health NHS Trust. There was no specific funding for this work.
Ethical approval
The extracted data consisted of deidentified routinely acquire patient data derived from general practitioner electronic health records with their permission as data controllers and reported as aggregate data. No ethical committee consent was required for such data uses.
Provenance
Freely submitted; externally peer reviewed.
Acknowledgements
The authors would like to thank Dr Ryan Beardsley for lending his expertise in data manipulation using R. The authors are also grateful to the GPs and their practice teams for allowing use of their patient records and to the Clinical Effectiveness Group for providing coding, advice, and access to these records, and maintenance of a high quality dataset with agreed coding entries.
Competing interests
The authors declare that no competing interests exist. | DIVALPROEX SODIUM | DrugsGivenReaction | CC BY | 33619016 | 19,419,409 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sarcoidosis'. | Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
Background
Sarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.
Case presentation
A 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.
Medical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.
Clinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.
Investigations
Laboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.
Differential diagnosis
Our patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.
Treatment
After failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.
Outcome and follow-up
Six months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.
Figure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.
Laboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).
Figure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.
Figure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.
Figure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).
A diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.
Discussion
In recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15
Secukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24
The apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.
Patient’s perspective
Since this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.
I developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.
All of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.
After my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.
Of course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.
My rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.
This has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.
Learning points
This is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).
IL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.
The paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.
Our case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.
Twitter: @ckirb19
Contributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.
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: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | SECUKINUMAB | DrugsGivenReaction | CC BY-NC | 33619146 | 19,002,719 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
Background
Sarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.
Case presentation
A 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.
Medical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.
Clinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.
Investigations
Laboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.
Differential diagnosis
Our patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.
Treatment
After failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.
Outcome and follow-up
Six months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.
Figure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.
Laboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).
Figure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.
Figure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.
Figure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).
A diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.
Discussion
In recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15
Secukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24
The apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.
Patient’s perspective
Since this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.
I developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.
All of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.
After my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.
Of course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.
My rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.
This has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.
Learning points
This is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).
IL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.
The paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.
Our case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.
Twitter: @ckirb19
Contributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.
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: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ADALIMUMAB, FOLIC ACID, METHOTREXATE, SECUKINUMAB, SULFASALAZINE | DrugsGivenReaction | CC BY-NC | 33619146 | 19,020,282 | 2021-02-22 |
What was the administration route of drug 'ADALIMUMAB'? | Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
Background
Sarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.
Case presentation
A 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.
Medical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.
Clinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.
Investigations
Laboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.
Differential diagnosis
Our patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.
Treatment
After failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.
Outcome and follow-up
Six months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.
Figure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.
Laboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).
Figure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.
Figure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.
Figure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).
A diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.
Discussion
In recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15
Secukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24
The apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.
Patient’s perspective
Since this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.
I developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.
All of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.
After my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.
Of course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.
My rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.
This has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.
Learning points
This is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).
IL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.
The paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.
Our case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.
Twitter: @ckirb19
Contributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.
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: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Subcutaneous | DrugAdministrationRoute | CC BY-NC | 33619146 | 19,020,282 | 2021-02-22 |
What was the administration route of drug 'FOLIC ACID'? | Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
Background
Sarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.
Case presentation
A 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.
Medical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.
Clinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.
Investigations
Laboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.
Differential diagnosis
Our patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.
Treatment
After failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.
Outcome and follow-up
Six months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.
Figure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.
Laboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).
Figure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.
Figure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.
Figure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).
A diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.
Discussion
In recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15
Secukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24
The apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.
Patient’s perspective
Since this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.
I developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.
All of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.
After my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.
Of course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.
My rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.
This has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.
Learning points
This is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).
IL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.
The paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.
Our case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.
Twitter: @ckirb19
Contributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.
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: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33619146 | 19,020,282 | 2021-02-22 |
What was the administration route of drug 'METHOTREXATE'? | Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
Background
Sarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.
Case presentation
A 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.
Medical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.
Clinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.
Investigations
Laboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.
Differential diagnosis
Our patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.
Treatment
After failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.
Outcome and follow-up
Six months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.
Figure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.
Laboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).
Figure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.
Figure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.
Figure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).
A diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.
Discussion
In recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15
Secukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24
The apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.
Patient’s perspective
Since this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.
I developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.
All of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.
After my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.
Of course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.
My rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.
This has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.
Learning points
This is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).
IL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.
The paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.
Our case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.
Twitter: @ckirb19
Contributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.
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: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Subcutaneous | DrugAdministrationRoute | CC BY-NC | 33619146 | 19,020,282 | 2021-02-22 |
What was the administration route of drug 'SECUKINUMAB'? | Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
Background
Sarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.
Case presentation
A 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.
Medical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.
Clinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.
Investigations
Laboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.
Differential diagnosis
Our patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.
Treatment
After failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.
Outcome and follow-up
Six months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.
Figure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.
Laboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).
Figure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.
Figure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.
Figure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).
A diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.
Discussion
In recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15
Secukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24
The apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.
Patient’s perspective
Since this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.
I developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.
All of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.
After my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.
Of course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.
My rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.
This has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.
Learning points
This is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).
IL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.
The paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.
Our case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.
Twitter: @ckirb19
Contributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.
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: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Subcutaneous | DrugAdministrationRoute | CC BY-NC | 33619146 | 19,002,719 | 2021-02-22 |
What was the administration route of drug 'SULFASALAZINE'? | Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
Background
Sarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.
Case presentation
A 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.
Medical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.
Clinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.
Investigations
Laboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.
Differential diagnosis
Our patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.
Treatment
After failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.
Outcome and follow-up
Six months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.
Figure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.
Laboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).
Figure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.
Figure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.
Figure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).
A diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.
Discussion
In recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15
Secukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24
The apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.
Patient’s perspective
Since this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.
I developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.
All of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.
After my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.
Of course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.
My rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.
This has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.
Learning points
This is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).
IL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.
The paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.
Our case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.
Twitter: @ckirb19
Contributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.
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: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33619146 | 19,020,282 | 2021-02-22 |
What was the outcome of reaction 'Sarcoidosis'? | Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.
Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.
Background
Sarcoidosis is a multisystem disorder characterised by the presence of non-caseating granulomata. While the disease is most commonly characterised by thoracic adenopathy, lung parenchyma, skin and articular disease, all organ systems may be affected. While the precise aetiology of sarcoidosis is unclear, numerous case reports of sarcoidosis occurring during the treatment with biological immunotherapies indicate that immune dysregulation plays a key role. Here, we describe a case of sarcoidosis developing following treatment with anti-interleukin-17A therapy (anti-IL-17A), which to our knowledge is the first such case.
Case presentation
A 52-year-old woman was referred to rheumatology outpatient clinic with new widespread peripheral joint and left buttock arthralgia and generalisation of palmoplantar psoriasis despite treatment with subcutaneous methotrexate 20 mg and folic acid 5 mg by mouth weekly.
Medical history was significant for an acute hospital admission 2 years previously with shortness of breath. CT pulmonary angiogram at that time revealed segmental collapse secondary to mucus plugging with no other abnormalities. Our patient was treated for asthma with long-acting beta agonist and corticosteroid inhalers.
Clinical examination revealed asymmetric synovitis of proximal interphalangeal (PIP), wrist and ankle joints (12 tender joints, 4 swollen joints), bilateral Achilles tendonitis with plantar fasciitis and marked tenderness of the left sacroiliac joint. A subtle degree of cutaneous plaque psoriasis was seen.
Investigations
Laboratory results showed a normal full blood count without oeosinophilia, elevated erythrocyte sedimentation rate (ESR) of 16 mm/hour (1–15), normal C-reactive protein (CRP) and normal rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP) and anti-neutrophil cytoplasm antibody titres. Plain radiographs of hands, feet and chest at this time were unremarkable and a diagnosis of active psoriatic arthritis was made.
Differential diagnosis
Our patient had a prior diagnosis of psoriasis, had active skin lesions and had an asymmetric oligoarthritis typical of psoriatic arthritis. Prior treatment with tumour necrosis factor-alpha inhibitor (TNFi) therapy and hilar adenopathy on CT raised the suspicion of both lymphoma and Mycobacterium tuberculosis infection. However, no B-symptoms were reported, serum lactate dehydrogenase (LDH) was within normal limits, interferon-gamma-release-assay was negative, hilar lymph node biopsies showed no evidence of malignancy and mycobacterial cultures from lymph node tissue were negative.
Treatment
After failed responses to sequential treatment with methotrexate 25 mg weekly in combination with sulphasalazine 1000 mg by mouth two times per day, followed by the TNFi adalimumab 40 mg s.c. (subcutaneous) fortnightly, articular and cutaneous remission was achieved with secukinumab 300 mg s.c. monotherapy weekly for 5 weeks, followed by once monthly.
Outcome and follow-up
Six months following secukinumab commencement, our patient represented with a new dry cough, exertional dyspnoea and recurrent polyarthralgia. Clinical examination and bedside ultrasound revealed finger dactylitis (figure 1A), bilateral knee synovitis and left-sided posterior tibialis tenosynovitis (figure 1B). A widespread violaceous rash affecting the eyelids, trunk and limbs was seen.
Figure 1 (A) Palmar longitudinal view of dactylitic finger showing tendon sheath effusion with power Doppler signal. (B) longitudinal view of posterior tibialis tendon showing tendon sheath effusion, tenosynovial thickening and power Doppler signal.
Laboratory markers showed elevated ESR (40 mm/hour) and CRP (20 mg/L). Chest X-ray was suggestive of lung nodularity with hilar enlargement and CT thorax demonstrated parenchymal solid and ground glass nodules with hilar and paratracheal lymphadenopathy (figure 2). Serum ACE (angiotensin-converting enzyme) and LDH were within normal limits and interferon-gamma-release-assay was negative. Pulmonary function tests (PFTs) showed a mild restrictive defect with transfer factor for carbon monoxide (TLCO) 80% predicted. Endobronchial ultrasound with biopsy of an affected lymph node and cutaneous biopsies confirmed the presence of non-necrotising granulomata (figures 3–4).
Figure 2 (A) Axial postcontrast CT image, soft tissue window, showing right hilar adenopathy (arrow). (B) CTPA from 2 years previously showing no adenopathy at that time. (C) Axial postcontrast CT image, soft tissue window, showing right lower paratracheal (white arrow) and left lower paratracheal (black arrow) adenopathy. (D) Comparative CTPA from 2 years previously showing no adenopathy at that time. CTPA, CT pulmonary angiogram.
Figure 3 Sarcoid at ×4. Dermis expanded by multiple non-caseating granulomata (white arrow), with foreign body giant cells (black arrows). No foreign material, micro-organism stains negative.
Figure 4 Sarcoid at ×20. Non-caseating granulomata (white arrow) with lymphocytic cuff (black arrow).
A diagnosis of multisystem sarcoidosis was made and prompt induction of remission was achieved using prednisolone 30 mg by mouth daily. Remission was maintained at a recent 3-month follow-up review at which point our patient was taking prednisolone 20 mg daily. This will be tapered by 5 mg monthly during regular follow-up and consideration will only be given to alternative biologic therapies in the event of a flare.
Discussion
In recent years, an increasing use of biological immunotherapies for autoimmune diseases has been associated with sporadic case reports of de novo sarcoidosis or exacerbations of pre-existing disease. While most frequently associated with TNFi, this phenomenon has also been observed following treatments that inhibit interleukin 2 (IL-2), IL-6, IL-12/23, IgE, alpha-integrin, cluster of differentiation 52 (CD-52), B-cells as well as with immune checkpoint inhibitors.1–11 Paradoxically, TNFi has also been used to treat various organ manifestations of sarcoidosis refractory to standard therapies indicating that a spectrum of immunopathology exists that requires future elucidation.12–15
Secukinumab is a human IgG1 monoclonal antibody that binds to the protein interleukin-17A. While there are no previous reports of sarcoidosis developing during treatment with secukinumab to our knowledge, treatment with IL-17A inhibition has been associated with the development, and exacerbation, of disease activity in other granulomatous diseases such as Crohn’s disease.16 Formation of sarcoid granulomas is thought to begin with foreign antigen presentation to CD4 +T helper lymphocytes which then stimulate the immune response via interferon-gamma, IL-2, TNF alpha and multiple other cytokines.17–22 The potential role for IL-17A in sarcoid pathogenesis has been suggested by the finding of increased IL-17A levels in bronchoalveolar lavage (BAL) fluid obtained from sarcoidosis patients while a case report showed significant improvement in a patient with TNFi-induced pulmonary sarcoidosis following anti-IL-17A therapy.23 24
The apparent association observed between IL-17 inhibition and granulomatous diseases such as Crohns, and now sarcoidosis, suggesting a common underlaying mechanism. Further understanding of this mechanism as well as understanding the apparent paradoxical effects observed with IL-17i in sarcoidosis is required to direct future individualised approaches to treatment of this complex multisystem inflammatory disease. Our case also highlights the importance for rheumatologists to continually monitor for de novo activation of other disease states, and indeed unforeseen reactivation of dormant disease states, in those with pre-existing inflammatory disease.
Patient’s perspective
Since this all started, I have lost my life as I knew it. I was an older woman but I was running, attending 3–4 gym classes per week, hill walking, playing golf, living life to the full and enjoying a social life too. I had met my now husband, and we had set up home together, after which I began to get sick.
I developed a rash on my buttocks and legs, then on my hands and feet and my dermatologist diagnosed psoriasis. My sister organised for me to see another dermatologist, who when I was there had checked my joints and said they were all inflamed. I was feeling pretty miserable and my feet were so painful to walk on. PUVA didn’t work and Methotrexate only worked for my skin, not my joints. A rheumatologist then diagnosed me with psoriatic arthritis and started me on adalimumab. At this point I could barley walk, my life had completely changed but I was trying to get on with it as I had recently got married. I had little or no response to the adalimumab so the rheumatologist put me on Secukinumab and this was a big change for me.
All of my joints began to ease within a couple of weeks and this felt like a new lease of life, I was feeling so well. I had taken back up my golf and it was great to be out in the air and feeling like I was in the land of the living. I was doing a spinning class as this was easier on my joints. I really thought “this is it”.
After my symptoms flared again, I was also diagnosed with sarcoidosis. When I think about it now, it was just another thing. But getting a diagnosis felt great, like ‘I know what I have now maybe they can start to treat everything that’s going on with me’. I was disappointed that I had to stop Secukinumab as this was the only thing that seemed to be working.
Of course there were frustrations, having to have different treatments but also there was hope that with each one this would be the one that worked, that gave me back my life. I was told I have both sarcoidosis and psoriasis, but to be honest all I was looking for was what treatment and what impact will this have on my life now, as I felt like I can’t do much more of this.
My rheumatologist admitted me to hospital for some tests. I had a biopsy on my arm and some scans. I was then told it was in my lungs and had an Endobronchial Ultrasound. I was started on 30 mg of steroids which have driven me quite mad I have to say. I’m up working (from home) between 3.00am and 4.00am. Most of my joints have freed up and I am beginning to feel a little more normal. As the steroids reduce, I am beginning to see and feel the benefits of them. I now have more energy and my brain doesn’t seem to be in a constant fog. All I hope is that it works. I’ve become quite anxious but of course that also is the medication. I am trying to keep my job going (I have a very understanding boss) and as for the rest of my life, I feel that its on hold.
This has taken me nearly 3 hours to write as I hadn’t realised how much this has affected my life. In the last few years, I have been just plodding along hoping that something would work. I have learnt that I am quite a strong person internally but something tells me if I shouted louder earlier maybe things would have been different. I’m still very hopeful that this will work.
Learning points
This is the first case reported of sarcoidosis manifesting during the treatment with secukinumab (anti-interleukin-17A, IL-17Ai).
IL-17Ai has been associated with the development of Crohn’s disease, suggesting a common underlaying mechanism between IL-17Ai and the development of granulomatous disease.
The paradoxical effects observed with IL-17i and sarcoidosis indicates that a spectrum of immunopathology exists that requires future elucidation to direct future individualised treatment approaches.
Our case highlights the importance for rheumatologists to continually monitor for de novo activation/reactivation of other disease states in those with pre-existing inflammatory disease.
Twitter: @ckirb19
Contributors: All listed authors contributed to this work. CK and RM were both involved in the clinical care of the patient and in acquiring ultrasound images. DH evaluated the radiological images and LC analysed biopsy specimens.
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: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33619146 | 19,002,719 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse.
BRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing was performed throughout the course of disease on tumor tissue from multiple sites, circulating tumor DNA from blood plasma, and matched normal tissue. Genomic analyses identified actionable variants for targeted therapies, as well as emerging resistance mutations over time. Two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) were identified upon resistance to PARP inhibitor and platinum treatment, respectively. Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients.
Introduction
Individuals with pathogenic germline BRCA1/BRCA2 alterations have an increased risk of breast, ovarian, pancreatic, prostate, and other cancers. Tumors that arise in these patients typically exhibit a somatic mutation, loss-of-heterozygosity (LOH), or epigenetic silencing in the wild-type BRCA allele, resulting in truncated or absent BRCA proteins and defective homologous recombination DNA repair1. This homologous recombination deficiency (HRD) renders DNA particularly vulnerable to damage caused by double-strand breaks, resulting in an accumulation of mutations over time and increased carcinogenesis2. However, HRD also renders BRCA1/2-mutant cancers sensitive to DNA-damaging agents, such as radiation3,4, platinum-based therapies5,6, and poly ADP-ribose polymerase (PARP) inhibitors7,8.
PARP inhibitors target the highly abundant proteins PARP1 and PARP2, which play an important role in transcription, chromatin modification, and DNA repair9. Therefore, PARP inhibition targets DNA repair through multiple mechanisms of action, including PARP trapping10,11, inhibition of base excision repair of single-strand breaks8, and indirect activation of non-homologous end-joining12–14. In tumors with HRD, such as those with BRCA alterations, PARP inhibition is especially effective because multiple DNA repair pathways are simultaneously impaired, resulting in synthetic lethality6–8.
In BRCA-mutant breast cancers, single-agent PARP inhibitor treatment induces partial response rates in as high as 47% of patients, and complete response lasting 60 weeks in up to 33% of patients15–17. Recent studies suggest response rates continue to improve with combined treatment regimens. However, despite initial effectiveness, BRCA-mutant cancers often develop resistance to PARP inhibition18,19. While many potential mechanisms for this resistance have been described, BRCA reversion mutations have emerged as a key resistance mechanism and have been described in a number of recent cases20–23. BRCA reversions occur when acquired somatic mutations, typically insertions/deletions (indels) or base substitutions, restore the open reading frame of the altered BRCA allele, resulting in a functional protein that restores efficient homologous recombination DNA repair. As a result, PARP inhibition no longer causes synthetic lethality, leading to drug resistance and disease progression.
Here we report the case of a patient with pathogenic germline BRCA2-driven breast cancer who acquired resistance to the PARP inhibitor olaparib. The resistance likely resulted from an acquired somatic reversion mutation, which was detected by matched tumor-normal genomic analysis. A second reversion mutation was also detected after carboplatin treatment through genetic sequencing of circulating tumor DNA (ctDNA) in blood plasma. This case highlights the benefits of longitudinal genomic testing, using multiple assay and tissue types including both tissue and blood plasma, to track the evolution of tumor mutations in order to provide the best treatment options for each patient based on their unique genomic profile.
Results
Patient history
At the age of 50, a female patient without regular mammography screening presented with a mass in her left breast (patient timeline shown in Fig. 1). Core biopsy of the mass demonstrated invasive ductal carcinoma that was ER+, PR−, and HER2− (immunohistochemistry (IHC), 1+). Based on the size of the tumor and evidence of lymph node involvement in magnetic resonance imaging (MRI), she received neoadjuvant chemotherapy including four cycles of doxorubicin and cyclophosphamide, followed by four cycles of paclitaxel. The patient then underwent bilateral mastectomy. Pathologic analysis of the left breast demonstrated 2.5 cm of residual malignancy, which was again found to be ER+, PR−. HER2 was 2+ (IHC) with HER2 ratio at 2.5 (fluorescence in situ hybridization (FISH)). At this time the patient started adjuvant tamoxifen treatment and completed a 1 year course of trastuzumab without complication. Germline testing revealed a pathogenic BRCA2 germline alteration, and the patient opted for a bilateral oophorectomy 2 years after starting tamoxifen. Her anti-estrogen therapy was changed to anastrozole, which she maintained for an additional 5 years. The patient palpated a mass in right axilla, but imaging workup did not show definitive evidence of malignancy or target for biopsy (mammogram, breast ultrasound, MRI, and positron emission tomography/computed tomography (PET/CT)).Fig. 1 Timeline of patient procedures, treatments, and disease progression.
Green boxes denote genomic testing, purple boxes denote treatments, and pink boxes denote clinical timepoints and diagnostic testing.
One year after cessation of anti-estrogen therapy and negative imaging workup, the patient developed pain in the right breast chest wall. Chest CT identified a lesion on the sternum and subsequent PET/CT demonstrated numerous bone metastases. A dominant lesion on the sternum was biopsied and demonstrated ductal carcinoma that was ER+, PR+ and HER2 1+ (IHC, FISH, respectively). Patient timeline is presented in Fig. 1.
Next-generation sequencing of metastatic bone lesion
At the time of the initial cancer diagnosis, next-generation sequencing (NGS) was not part of a typical clinical workup. Due to a difference in 10 years between primary diagnosis and metastatic disease, with evidence of clinical utility and a change in hormone status, the metastatic lesion was sent for NGS sequencing. The tumor-normal matched genomic analysis of the metastatic bone lesion and blood sample confirmed the presence of the known germline BRCA2 alteration (p.E260fs, c.778_779del, ClinVar variation ID 38119, Fig. 2a, b). Somatic loss-of-heterozygosity in BRCA2 was not detected in sequencing results of the metastatic bone lesion. In addition to the BRCA2 alteration, copy number gains in CDK4 and MYC were also identified. The patient was treated with fulvestrant and palbociclib for 1 year, at which time she developed progression. She was briefly treated with an experimental estrogen partial agonist, but progressed shortly after. At this point, the patient began treatment with PARP inhibitor olaparib, based on the germline BRCA2 alteration.Fig. 2 Evolution of BRCA2 alterations over time.
Integrative Genomics Viewer (IGV) visualization of BRCA2 sequencing data. a, b Genomic analysis of whole blood and tumor tissue from a bone metastasis reveals a 2 base pair (bp) deletion in both, indicating a germline alteration. c Genomic analysis of a metastatic liver lesion reveals both the original 2 bp deletion, as well as an additional 7 bp deletion, resulting in an in-frame somatic reversion. d, e Genomic analysis of circulating tumor DNA (ctDNA) from blood plasma shows the previously identified germline alteration and somatic reversion alteration, as well as a secondary somatic reversion mutation. Horizontal pink and blue bars are individual reads denoting forward and reverse strand sequence orientation, respectively. Gray histogram indicates relative sequencing coverage at the individual nucleotide position. A decrease in coverage is expected at the location of the deletions. Nucleotide deletions are represented as short horizontal black bars with the size of the deletion specified below the sequencing reads. Reference nucleotide sequence is indicated. Reference protein sequence at the bottom is in blue with single letter abbreviations for the amino acids and the intron depicted with a thin blue line and arrows showing directionality. The three possible open reading frames are in gray, with the third being the wild-type reading frame.
Next-generation sequencing of metastatic liver lesion reveals BRCA2 reversion mutation after clinical resistance to PARP inhibition
While the patient initially responded well to PARP inhibition, she developed liver metastases after 9 months. Genomic analysis of a metastatic liver lesion revealed the original germline alteration. A somatic alteration was also detected in BRCA2 at a variant allele frequency (VAF) of 18.1%, which was in cis (on the same allele) with the pathogenic germline alteration. This somatic alteration (p.N255fs, c.764_770del) in combination with the germline frameshift resulted in an in-frame indel and subsequent restoration of the BRCA2 reading frame (p.N255_R259delinsIK, c.764_776delinsTCAA), likely accounting for the resistance to PARP inhibition (Figs 2c and 3). The patient was then started on carboplatin and gemcitabine with excellent response in liver metastases and continued on maintenance therapy.Fig. 3 Multiple BRCA2 reversion mutations restore open reading frame of germline alteration.
a The BRCA2 protein diagram, protein domains, and number of amino acids. b The wild-type nucleotides and amino acids for amino acids 250–264, encompassing the region of germline and somatic alterations. c A 2 base pair (bp) deletion causes a frameshift in BRCA2 in the germline. d A somatic deletion of 7 bp causes a reversion mutation that restores the open reading frame of the germline alteration. e A 4 bp deletion causes a second somatic reversion mutation, which also restores the open reading frame altered by the germline alteration.
Next-generation sequencing of circulating tumor DNA reveals second unique BRCA2 reversion mutation
A liquid biopsy from blood plasma was obtained 5 months later for ctDNA sequencing. The genomic analysis identified the known somatic and germline BRCA2 alterations (1% and 53.4% VAF, respectively), as well as an additional unique somatic BRCA2 alteration (p.D252fs, c.755_758del) at 0.9% VAF. The secondary somatic BRCA2 mutation was also in cis with the pathogenic germline alteration, but in trans with the first somatic reversion mutation. The second somatic mutation in combination with the germline frameshift resulted in an in-frame indel and thus represented a second subclonal reversion mutation (Figs 2d, e and 3). Additionally, the liquid biopsy revealed pathogenic variants in ESR1 (p.Y537S, c.1610A > C) and TP53 (p.G266V, c.797 G > T). Due to elevated tumor mutational burden (TMB) in the patient’s first sequencing results, and the possibility that previous therapies may have contributed to the development of neoantigens, the patient briefly underwent immunotherapy with one cycle of ipilimumab and nivolumab therapy. However, liver function worsened and so the therapy was discontinued. Shortly after discontinuation, the patient passed away at the age of 63.
Discussion
Here we report a case of longitudinal diagnostic testing methodology using multiple assay and tissue types. This patient acquired resistance to PARP inhibitor olaparib, a result of a somatic BRCA2 reversion mutation that restored the open reading frame of a germline frameshift alteration. This case is consistent with recent reports of BRCA reversions in both germline and somatic alterations reported in prostate cancer, ovarian cancer, and breast cancer after treatment with PARP inhibitors, which were associated with resistance to treatment20–22,24,25. However, in most studies to date, the timing and mechanism of the reversion alterations remain unclear due to a lack of longitudinal testing that started before the reversion alteration appeared. Indeed, many patients receive different lines of treatment or neoadjuvant therapies before PARP inhibitor treatment that may induce the accumulation of mutations26,27. It is possible, a small population of a clone with a reversion mutation could exist in a patient for years, and once PARP inhibition is initiated that clone is selected for and becomes the dominant clone.
This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and highlights the utility of combined tissue/normal/blood biopsies in routine care of patients with cancer. For example, genomic analysis of tumor-normal matched samples enables a more thorough understanding of germline and somatic alterations and can identify co-existing actionable variants that may have been overlooked in standard genetic tests. In addition to the previously identified germline BRCA alteration in this case, CDK4 and MYC copy number alterations were identified by NGS of matched tumor-normal tissue, informing subsequent treatment decisions. Indeed, CDK4 inhibition with palcociclib allowed for a year of successful treatment before treatment with PARP inhibitor olaparib began.
Like many patients with BRCA-mutant cancers, this patient initially responded favorably to PARP inhibition. However, after 9 months of PARP inhibitor therapy, the patient was diagnosed with progressive disease and metastasis to the liver. Genomic analysis of the liver metastasis revealed a somatic reversion mutation absent from the previous bone metastasis biopsy. This somatic reversion restored the open reading frame in tumor cells, enabling the synthesis of an in-frame BRCA2 protein and efficient DNA repair through homologous recombination, which is consistent with the resistance to PARP inhibitor treatment this patient experienced.
Additionally, this patient received a liquid biopsy that identified a second reversion alteration several months after identification of the first somatic reversion in a solid tumor biopsy. It is unclear whether the second subclonal mutation was present in another tumor site when the first reversion was identified, if it was acquired after discontinuation of PARP inhibition, or in response to the platinum treatment as has been previously documented24,28. While reliable at identifying driver alterations in solid tumors, due to the heterogeneous nature of tumors and emerging resistance mutations, genomic solid tissue analysis can be somewhat limited in detecting the diversity of mutations associated with advanced cancers. Indeed, many studies have identified actionable mutations in metastatic lesions that were not present in the primary tumors29–31. Because tumor cells from multiple locations can shed DNA into the blood, liquid biopsies can detect alterations present in distant metastases. As such, analysis of ctDNA from liquid biopsies is increasingly used in combination with solid tissue analyses.
Critical questions remain in the treatment of BRCA-mutant cancers. For example, for which patients should serial genomic testing be performed, and how should reversion alterations impact clinical decision-making? While ideally all patients would have access to serial genomic testing, in reality this is unlikely to be feasible in the near future due to cost and availability. However, serial testing will be particularly relevant for patients taking drugs with known resistance mechanisms, such as PARP inhibitors and platinum-based therapies. How reversion alterations may affect clinical decision-making likely depends on whether the reversion was detected in the tumor tissue or in blood plasma (liquid biopsy). For example, if a reversion alteration is detected through liquid biopsy, but not in the tumor tissue biopsy, continuation of PARPi treatment seems reasonable. However, the patient would benefit from being more closely monitored, as the identification of the reversion alteration in cfDNA indicates imminent progression.
In conclusion, serial NGS sequencing with multiple assays and sample types, including paired solid tumor/normal and liquid biopsy, revealed the evolution of BRCA reversions, the genetic source of resistance, as well as additional actionable variants for targeted therapy. This demonstrates the value of routine genomic testing in clinical care of oncology patients for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes.
Methods
xT sample processing and nucleic acid extraction
Overall tumor content and percent tumor cellularity as a ratio of tumor-to-normal nuclei verified specimens met a 20% threshold. Solid tumor total nucleic acid was extracted from FFPE tissue sections using Chemagic 360 sample-specific extraction kits (Perkin Elmer) and digested by proteinase K.
xT panel DNA library construction and sequencing
DNA sequencing of 596 genes was performed as previously described32,33. Briefly, 100 ng of DNA was mechanically sheared to an average size of 200 base pair (bp) using a Covaris Ultrasonicator. KAPA Hyper Prep Kit was used to prepare DNA libraries, which were then hybridized to the xT probe set, and amplified with the KAPA HiFi HotStart ReadyMix. Library preps were hybridized to xGEN Exome Research Panel v1.0 (Integrated DNA Technologies) and target recovery was performed using Streptavidin-coated beads. This was followed by amplification with the KAPA HiFi Library Amplification Kit. The amplified target-captured library was sequenced using 2 × 126 bp paired-end (PE) reads to an average unique on-target depth of 500× (tumor) and 150× (normal) on an Illumina HiSeq 4000. Samples were evaluated for uniformity and verified to have 95% of all targeted bp sequenced to a minimum depth of 300×.
xF sample processing and nucleic acid extraction
Whole blood samples were collected in Streck Cell-Free DNA BCT (blood collection tubes) and centrifuged to separate plasma and buffy coat. Plasma was centrifuged a second time to remove any cellular or platelet carryovers. Plasma hemolysis was scored and reviewed by a pathologist prior to cfDNA extraction. cfDNA was isolated using the Qiagen QIAamp MinElute ccfDNA Midi Kit and the QIAcube system. The Fragment Analyzer was used to evaluate the quality of the extracted cfDNA. Quality was verified by the presence of a primary peak at approximately 150 bp and minimal to no genomic DNA (gDNA) peaks.
xF panel cfDNA library construction and sequencing
The xF assay is a 105-gene hybrid capture NGS panel designed to detect actionable oncologic targets in plasma. Briefly, a minimum of 30 ng of cfDNA is required as input for library preparation. cfDNA libraries were prepared using the New England BioLab’s NEBNext® Ultra™ II DNA Library Prep Kit for Illumina®, hybridized to the xF probe set, captured using Streptavidin-coated beads, and amplified with the KAPA HiFi Library Amplification Kit. The amplified target-captured cfDNA library was sequenced using 2 × 151 bp PE reads to an average unique on-target depth of 4500× on an Illumina NovaSeq 6000.
Variant detection, visualization, and reporting
Variant detection, visualization, and reporting were performed as previously described32,33. Briefly, adapter-trimmed FASTQ files were aligned to the 19th edition of the human reference genome build (hg19) using Burrows-Wheeler Aligner (BWA). Following alignment, reads were grouped by alignment position and UMI family, and collapsed into consensus sequences using fgbio tools. SNV and indel variants were detected using VarDict. Copy number variants (CNVs) were analyzed using CNVkit15 plus a Tempus CNV annotation and filtering algorithm. Rearrangements were detected using the SpeedSeq analysis pipeline. Gene rearrangements were analyzed by LUMPY. Data were visualized using Integrative Genomics Viewer (IGV)34. Individual reads in IGV were colored pink or blue, based on forward or reverse orientation, respectively. Reads containing the deletion variants were sorted to the top for visualization and cis and trans calls were made manually.
Ethics statement
We have complied with all ethical regulations. This is a case report of one patient, and she did not receive any experimental procedures or treatments as part of this study. As this is a retrospective analysis of data obtained through standard treatment protocols, this case does not require IRB approval. Written informed patient consent for clinical testing, analysis, and publication was obtained by Tempus Laboratories.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Supplementary information
Reporting Summary
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41525-021-00181-0.
Acknowledgements
The authors acknowledge Matthew Kase and Robert Huether for critical evaluation of this manuscript.
Author contributions
C.S. was the treating oncologist for the patient. C.S. and S.S. conceived of and designed the study. A.M. and S.S. performed molecular and clinical analyses. C.S., K.E.M., and S.S. wrote the manuscript. K.E.M. and S.S. designed and assembled figures. All authors reviewed, edited, and approved of the manuscript.
Data availability
All relevant data supporting the findings of this study are included in the published article.
Competing interests
S.S., K.E.M., and A.M. were employed by Tempus Labs when this work was performed. C.S. declares no competing interests. | CARBOPLATIN, GEMCITABINE, OLAPARIB | DrugsGivenReaction | CC BY | 33619265 | 19,694,252 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bone disorder'. | First prospective data on breast cancer patients from the multicentre italian bone metastasis database.
Bone metastases (BM) are still the main cause of morbidity in cancer patients because of skeletal-related events (SREs) that reduce quality of life. They have also led to increased social and healthcare costs. At present, data available on BM are insufficient. This was a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 months' follow-up. Information on patients at the first diagnosis of BM, including demographics and characteristics of the primary tumor and BM. Data were periodically updated by participating centres and reviewed by the coordinator centre. From October 2014 to July 2019, 618 patients with BM from solid tumors were enrolled and 220 were eligible for the present study. Median age was 62 years (range 26-86). Median follow-up was 34 months (range 6-149). At the time of enrolment, 109 (50%) had only BM (BOM) and 109 (50%) had concomitant visceral lesions and BM (BVM). Median time-to-first BM was 47 months (range 0-312) in BOM and 78.6 months in BVM patients. Disease-free interval differed on the basis of BC molecular subtype and stage. Ninety-eight BM patients had at least on SRE. Zoledronate was used in 69.1% of cases and denosumab in 28.3%. First-line treatment was hormone-based (50.7%), chemotherapy-based (38.7%) or chemotherapy- + hormone therapy-based (9.7%). Median progression-free and overall survival were 15.1 months (95% CI 12.6-18.4) and 66.8 months (95% CI 52.1-79.2), respectively. Our prospective study could substantially help to better understand the natural history of BM from BC.
Introduction
Breast cancer (BC) is the most common malignancy and a major cause of morbidity and mortality among women. The mortality rate has decreased thanks to improved diagnostic procedures, screening and more advanced treatments. However, the rate of recurrence in distant organs is still fairly high, ranging from 20 to 30%1,2.
Bone is the most common site of metastasis in BC and significantly impacts patient survival3–5.
Bone metastases (BMs) represent an important clinical-epidemiological issue in oncology because their diagnosis and treatment are often necessarily handled by several specialists, resulting in fragmented patient information6. For these reasons, great efforts have been made to develop a new scientific and clinical branch of medicine, i.e. Osteoncology7.
The major problem faced by BM patients is the risk of skeletal complications defined as skeletal-related events (SREs) all of which are highly detrimental to quality of life and survival2,8,9.
There is still limited information available on BM clinical presentation, the difference in disease response between bone and visceral sites, and the difference in prognosis between solitary, oligometastatic and multiple sites or axial and trunk bone metastases10. A clearer understanding of their natural evolution would thus help us to identify new strategies capable of reducing both BM incidence and morbidity.
The risk of SREs in BC patients with BM has been the focus of numerous studies11–13. However, their findings are of limited value because of their poor generalizability with respect to current clinical practice. In the retrospective studies, authors usually considered a lengthy time period during which available therapies and clinical practice may have changed substantially. In the prospective studies, patients were followed for a short period (24 months) and data were extrapolated from a BC database rather than from a database dedicated to BM. Furthermore, in recent years, new therapeutic options have become available. There has also been growing interest in BM since dedicated multidisciplinary groups began to emerge14.
The main aims of this prospective multicenter study were to evaluate the evolution of skeletal disease in BC patients, assess the impact of BM on disease outcome, examine the role of a number of clinical-pathological parameters in predicting survival, and further our understanding of the natural history of patients with BM from BC.
Materials and methods
This was a multicentre prospective observational study of patients with BM from BC with at least 6 months follow-up, enrolled into the prospective Italian Bone Metastases Data Base (BMDB). The study was approved by the Local Ethics Committee of each participating centre and carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. List of participating centers was provided in Supplementary Table 1. Written informed consent was obtained from all patients. Information on data source is provided in Appendix 1.
Data extraction and measure definition
The evolution of skeletal disease in BC patients was evaluated by extracting data from the BMDB for patients who had a first diagnosis of BC with a synchronous (within 2 months) or metachronous diagnosis of bone metastasis and were followed up for at least 6 months after the BM diagnosis.
Time to event outcomes were defined as follows: disease-free interval (DFI) was the time from primary BC disease to the appearance of the first metastasis (bone or visceral), and bone disease-free interval (bDFI) was the time between diagnosis of primary BC and first diagnosis of BM. Overall survival (OS) was calculated as the time from the date of the diagnosis of primary BC to the date of death. OS from metastatic disease (metOS) was calculated as the time from the diagnosis of metastasis (either bone or visceral) to death. Progression-free survival (PFS) was the time between the date of the first diagnosis of bone metastasis and date of the first documented evidence of disease progression (bone or visceral) and death. Bone PFS (bPFS) was the time between the date of the first diagnosis of BM and first progression to bone and death. Time-to-first SRE was the time between the first diagnosis of BM and the first SRE event. Patients without events of interest were censored at the date of the last follow-up visit.
Statistical analysis
Descriptive statistics are used to summarize baseline patient characteristics, BM characteristics and treatment patterns. Continuous variables are presented using median and range or interquartile range. The Wilcoxon rank-sum test was used for continuous variables, together with the chi-squared test or Fisher’s exact test, as appropriate. McNemar’s test was used in cases of paired data. Time-to-event measures were analysed using the Kaplan–Meier method, and the nonparametric log-rank test was used to evaluate the role of stratification factor. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) and relative 95% confidence intervals (CI) of potential clinical prognostic factors for time-to-event outcomes.
All statistical analyses were performed using STATA/MP 15.0 for Windows (StataCorp LLP, College Station, TX, USA).
Results
Patient characteristics
From October 1st 2014 to June 30th 2018, 618 patients with BM from any solid tumor were registered in the Italian BMDB. Three hundred and nine had BC as the primary site of disease and 220/309 with at least 6 months’ follow up were included in the present analysis (Fig. 1). Median age was 62 (range 26–85) years.Figure 1 Study flow diagram.
At the time of the first diagnosis of BM, 152 (92.1%) patients showed a good ECOG PS (0–1). Forty-nine (22.3%) patients were diagnosed with BM synchronous to the primary tumor, while metachronous BM were found in 171 patients.
Bone-only metastases (BOM) were found in 109 (50.0%) patients, while the remaining 109 had concomitant visceral and BM (BVM). Histological and biological characteristics of the primary BC are shown in Tables 1 and 2. Luminal A and B tumors were more frequently associated with BOM, whereas basal-like or HER2-enriched BC subtypes more often showed BVM (p = 0.012). A higher, albeit not significant, Ki-67 value was observed for patients with BVM (p = 0.074). The majority of patients had T0-T2 (n = 159, 85%) and node-positive tumors (n = 138, 74.6%) at diagnosis (Table 3), the former associated with a higher rate of metachronous BM than synchronous BM (83.2% and 16.8%, respectively) (p < 0.001) (Table 4). Patients with N0 primary tumors had a higher incidence of metachronous BM than synchronous (95.8% and 4.2%, respectively) (p = 0.001). No difference between BOM or BVM according to node status (node negative vs. node positive tumors) was observed. Both node-negative and node-positive patients showed a high rate of metachronous BM (95.8% and 75.5%, respectively), even if in node-negative patients there is a significantly higher proportion of patients with metachronous BM.Table 1 Patient characteristics at baseline and at onset of BM.
Patients (n = 220)
Median age, years (range) 62 (26–85)
No. (%)
Age at diagnosis of primary BM, years
< 65 133 (60.5)
65 87 (69.5)
ECOG PS at diagnosis of primary BM
0–1 152 (92.1)
≥ 2 13 (7.9)
Unknown 55
Histology
Ductal carcinoma 166 (75.5)
Lobular carcinoma 29 (13.0)
Mixed ductal and lobular carcinoma 11 (5.0)
Adenocarcinoma, NOS 9 (4.0)
Signet ring cell carcinoma 1 (0.5)
Other 4 (2.0)
pT at primary diagnosis of BC
T0–T2 159 (85.0)
T3–T4 28 (15.0)
Tx 31
pN at primary diagnosis of BC
N0 47 (25.4)
N+ 138 (74.6)
Nx 33
Stage at diagnosis of primary disease
I 28 (14.1)
II 68 (34.3)
III 42 (21.2)
IV 60 (30.3)
Unknown 22
BC molecular subtype
Luminal A 35 (18.8)
Luminal B 118 (63.4)
Basal-like 8 (4.3)
HER+ 25 (13.4)
Unknown 34
Grading
G1 6 (3.7)
G2 85 (52.5)
G3 71 (43.8)
Unknown 58
Bone metastasis
Synchronous 49 (22.3)
Metachronous 171 (77.7)
BOM 109 (50.0)
BVM 109 (50.0)
BM bone metastasis, ECOG PS Eastern Cooperative Oncology Group Performance Status, NOS not otherwise specified, BC breast cancer, pT primary tumour, pN pathological lymph node, Nx unknown lymph node stage, G grade, BOM bone-only metastasis, BVM visceral and bone metastasis.
Table 2 Biomarker characteristics at diagnosis of primary BC and at onset of BM.
BC characteristics At diagnosis At the onset of bone metastasis
Positive* (%) Negative* (%) NA Positive* (%) Negative* (%) NA
ER 183 (89.7) 21 (10.3) 16 48 (88.9) 6 (11.1) 166
PgR 144 (70.6) 60 (29.4) 16 24 (45.3) 29 (54.7) 167
< 15% ≥ 15% NA < 15% ≥ 15% NA
Ki-67 145 (79.7) 37 (20.3) 38 29 (65.9) 15 (34.1) 176
Positive/(+ + +) Negative/0–2 + NA Positive/(+ + +) Negative/0–2 + NA
HER2 (IHC or FISH) 24 (12.9) 162 (87.1) 34 7 (13.7) 44 (86.3) 169
BC breast cancer, BM bone metastasis, ER oestrogen receptor, PgR progesterone receptor, NA not available, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
*For ER and PgR, positive if ≥ 10%, negative if < 10%.
Table 3 Baseline patient characteristics in relation to presence of visceral metastases.
Baseline BC characteristics No. patients
(n = 218) BOM (n = 109)
No. (%) BVM (n = 109)
No. (%) p-value
Age at diagnosis of bone metastasis, years
< 65 108 (49.1) 70 (53.0) 62 (47.0) 0.268
≥ 65 112 (50.9) 39 (45.3) 47 (54.7)
pT at primary diagnosis of breast cancer
T0–T2 159 (85.0) 84 (52.8) 75 (47.2) 0.531
T3–T4 28 (15.0) 13 (46.4) 15 (53.6)
pN at primary diagnosis of breast cancer
N0 47 (25.4) 26 (55.3) 21 (44.7) 0.330
N+ 138 (74.6) 65 (47.1) 73 (52.9)
Stage at diagnosis of primary disease
I 27 (13.8) 16 (59.3) 11 (40.7) 0.621
II 67 (34.2) 31 (46.3) 36 (53.7)
III 42 (21.4) 23 (54.8) 19 (45.2)
IV 60 (30.6) 33 (55.0) 27 (45.0)
Unknown 22 6 16
Breast cancer molecular subtype
Luminal A 35 (19.0) 26 (74.3) 9 (25.7) 0.012
Luminal B 118 (64.1) 60 (50.8) 58 (49.2)
Basal-like 7 (3.8) 2 (28.6) 5 (71.4)
HER+ 24 (13.1) 9 (37.5) 15 (62.5)
Unknown 34 12 22
Median Ki67% (interquartile range) 20 (10–31) 16 (8–30) 20 (10–35) 0.074
ER
Negative 19 (9.4) 6 (31.6) 13 (68.4) 0.075
Positive 183 (90.6) 97 (53.1) 86 (46.9)
Unknown or not performed 16 6 10
PgR
Negative 58 (28.7) 29 (50.0) 29 (50.0) 0.858
Positive 144 (71.3) 74 (51.4) 70 (48.6)
Unknown or not performed 16 6 10
HER2 (IHC or FISH)
Negative 161 (87.5) 89 (55.3) 72 (44.7) 0.066
Positive 23 (12.5) 8 (34.8) 15 (65.2)
Unknown or not performed 34 12 22
Adjuvant therapy
No 73 (33.4) 35 (47.9) 38 (52.1) 0.632
Yes 144 (66.1) 74 (51.4) 70 (48.6)
Neoadjuvant therapy
No 196 (91.2) 97 (49.5) 99 (50.5) 0.484
Yes 19 (8.8) 11 (57.9) 8 (42.1)
BC breast cancer, BOM bone-only metastasis, BVM visceral and bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
Table 4 Baseline patient characteristics in relation to synchronous or metachronous metastases.
Baseline BC characteristics No. patients
(n = 220) Synchronous BM
(n = 49)
No. (%) Metachronous BM
(n = 171)
No. (%) p-value
Age at diagnosis of bone metastasis, years
< 65 133 (49.1) 32 (24.1) 101 (75.9) 0.431
≥ 65 87 (50.9) 17 (19.5) 70 (80.5)
pT at primary diagnosis of breast cancer
T0–T2 161 (85.0) 27 (16.8) 134 (83.2) < 0.001
T3–T4 28 (15.0) 15 (53.6) 13 (46.4)
pN at primary diagnosis of breast cancer
N0 48 (25.6) 2 (4.2) 46 (95.8) 0.001
N+ 137 (74.3) 34 (24.5) 105 (75.5)
Stage at diagnosis of primary disease
I 28 (14.1) 0 (0.0) 28 (100.0) –
II 68 (34.4) 0 (0.0) 68 (100.0)
III 42 (21.2) 0 (0.0) 42 (100.0)
IV 60 (30.3) 49 (81.7) 11 (18.3)
Unknown 22 – 22
Breast cancer molecular subtype
Luminal A 35 (18.8) 7 (20.0) 28 (80.0) 0.315
Luminal B 118 (63.4) 31 (26.3) 87 (73.7)
Basal-like 8 (4.3) 1 (12.5) 7 (87.5)
HER+ 25 (13.4) 10 (40.0) 15 (60.0)
Unknown 34 – 34
Median Ki67% (interquartile range) 20 (10–31) 23 (15–35) 16 (10–30) 0.087
ER
Negative 21 (9.9) 2 (9.5) 19 (90.5) 0.114
Positive 183 (90.1) 47 (25.7) 136 (74.3)
Unknown or not performed 16 – 16
PgR
Negative 60 (29.4) 11 (18.3) 49 (81.7) 0.220
Positive 144 (70.6) 38 (26.4) 106 (73.6)
Unknown or not performed 16 – 16
HER2 (IHC or FISH)
Negative 162 (87.1) 38 (23.5) 124 (76.5) 0.057
Positive 24 (12.9) 10 (41.7) 14 (58.3)
Unknown or not performed 34 1 33
BM bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
Bone biopsy was performed in 58 (26.4%) cases. The median time from primary disease diagnosis to the appearance of BM in this subgroup was 79 months (95%CI: 65.0–118.1).
Time to event outcomes
Disease-free interval
Disease free-interval was calculated excluding patients with synchronous disease at bone (n = 49) and visceral (n = 2). The disease-free interval (DFI) differed slightly according to molecular subtype. The univariate hazard ratio (HR) for visceral or bone metastasis was higher in luminal B tumors (1.66, 95% confidence interval [CI] 1.1–2.5) (p = 0.023), basal-like tumors (3.92, 95% CI 1.6–9.7) (p = 0.003), and HER2-enriched tumors (1.28, 95% CI 0.7–2.4) (p = 0.442).
DFI for patients with stage I disease at diagnosis of primary BC was longer than that for stage III patients (median 67.2 months, 95% CI 53.1–96.1, vs. 58.1 months, 95% CI 41.9–73.4), with a univariate HR of 1.84 (95% CI 1.1–3.0) (p = 0.015) for the stage III group, and 0.98 (95% CI 0.6–1.5) (p = 0.931) for the stage II group. Older patients had a higher risk of metastasis (HR 1.91, 95% CI 1.4–2.7), as did those with larger tumors at diagnosis (HR: 3.7, 95% CI 1.9–7.1). Multivariate analysis confirmed these data for patients with basal-like and larger tumors (Table 5).Table 5 Median DFI and independent risk factors for metastasis.
Overall DFI bDFI
Median
(95%CI) HR from univariate Cox regression model (95%CI) HR from multivariate Cox regression model (95%CI) Median
(95%CI) HR from univariate Cox regression model (95%CI) HR from multivariate Cox regression model (95%CI)
All cases 75.7 (63.5–87.3) – – 78.2 (63.6–87.9) – –
Age at diagnosis of primary BC, years
< 55 82.1 (65.4–112.9) 1.00 1.00 89.6 (65.4–114.8) 1.00 1.00
≥ 55 65.0 (48.1–81.5) 1.91 (1.4–2.7) 1.48 (0.9–2.2) 65.0 (51.1–86.0) 1.89 (1.4–2.6) 1.27 (0.9–1.9)
BC molecular subtypes
Luminal A 101.9 (57.0–125.7) 1.00 1.00 101.9 (57.0–125.7) 1.00 1.00
Luminal B 63.5 (48.6–75.7) 1.66 (1.1–2.5) 1.46 (0.9–2.4) 63.6 (52.7–78.5) 1.54 (0.9–2.4) 1.27 (0.8–2.0)
Basal-like 30.0 (13.4–NE) 3.92 (1.6–9.7) 3.94 (1.4–11.0) 30.0 (2.1–66.1) 4.29 (1.8–10.1) 3.82 (1.4–10.6)
HER2+ 53.1 (30.9–100.1) 1.28 (0.7–2.4) 1.44 (0.7–2.9) 53.1 (47.9–100.2) 1.17 (0.6–2.2) 1.22 (0.6–2.5)
Stage at diagnosis
I 67.2 (53.1–96.1) 1.00 1.00 82.2 (53.6–125.7) 1.00 1.00
II 83.3 (66.5–99.2) 0.98 (0.6–1.5) 1.09 (0.5–2.3) 83.2 (66.5–101.9) 1.07 (0.7–1.7) 1.16 (0.6–2.4)
III 58.1 (41.9–73.4) 1.84 (1.1–3.0) 1.35 (0.5–3.2) 60.9 (41.9–75.6) 2.1 (1.3–3.5) 1.55 (0.7–3.7)
IV – – – – – –
pT at primary diagnosis of BC
T0–T2 76.7 (61.0–87.3) 1.00 1.00 78.5 (63.6–87.9) 1.00 1.00
T3–T4 20.6 (3.3–65.4) 3.7 (1.9–7.1) 3.24 (1.5–7.1) 18.6 (3.3–57.0) 4.5 (2.4–8.2) 3.02 (1.4–6.6)
pN at primary diagnosis of BC
N0 83.3 (56.1–101.9) 1.00 1.00 89.6 (61.1–118.2) 1.00 1.00
N+ 66.5 (56.3–80.0) 1.36 (0.9–1.9) 0.91 (0.5–1.7) 66.5 (57.0–79.0) 1.47 (1.0–2.1) 0.97 (0.5–1.8)
DFI disease-free interval, bDFI bone disease-free interval, HR hazard ratio, BC breast cancer, NE not evaluable from statistical software, pT primary tumour, pN pathological lymph node.
Bone disease-free interval
For this analysis, were excluded all patients with synchronous bone metastasis (n = 49). Median time to BM appearance was 78.2 months (95% confidence interval [CI] 63.6–87.9) for all patients.
Median bone disease-free interval (bDFI) was 63.5 months (95% CI 47.9–83.3) for the BM-only group at diagnosis and 86.6 months (95% CI 66.5–99.6) for those with visceral metastases. Median bDFI was 78.5 months (95% CI 63.6–87.9) in T0–T2 patients and 18.6 months (95% CI 3.3–57.0) in the T3–T4 group (p ≤ 0.001). The group with node-negative BC had a median bDFI of 8.6 months (95% CI 61.1–118.2) compared to 66.5 months (95% CI 57.0–79.0) for the node-positive subgroup (log rank test p = 0.032) (Fig. 2a,b). bDFI was significantly higher (p < 0.001) in patients aged < 55 years at diagnosis than in those ≥ 55 years, (median 89.6 [95% CI 65.4–114.8] vs. 65.0 [95% CI 51.1–86.0] months) (Supplementary Fig. 1). Multivariate analyses confirmed a higher risk for patients with basal-like and larger tumors (Table 5).Figure 2 Disease-free interval by (a) T and (b) N of primary disease.
Overall survival
Median follow-up was 46 months (range: 6–117) on 220 evaluable patients.
Seventy-four deaths were observed during follow-up. Median OS was 217.5 months (95% CI 172.5–340.1).
Molecular profile subtypes were an independent prognostic factor. Median OS (mOS) in patients with luminal A tumors was not-reached and 128.1 months (95% CI 108.0–182.6) for those with luminal B tumors, 101.2 months (95% CI 17.1–not estimable) for patients with basal-like BC, and 274.5 months (95% CI 70.3-–not estimable) for those HER2-enriched BC (p = 0.010). Patients aged ≥ 55 years and those with stage IV disease at diagnosis had a shorter mOS (128.1 months [95% CI 101.2–182.6] and 65.3 months [95% CI 41.0–80.9], respectively) than the groups diagnosed at a younger age (< 55 years) and with lower-stage disease (Supplementary Fig. 2a,b). Patients with pain at the first diagnosis of bone metastases had an mOS of 143.8 months (95% CI 98.0–247.5) with respect to 257.4 months (95% CI 135.1–not estimable) for those with no pain. mOS of the group with axial BM was 252.5 months (95% CI 182.5–343.0), 157.6 months (95% CI41.0–Not estimable) for those with appendicular BM, and 217.5 months (95% CI 100.9–Not estimable) for patients with both types of metastases (p = 0.009).
mOS of patients undergoing first-line treatment was 135.1 months (95% CI 102.9–257.4) for the chemotherapy (CH) ± biological therapy (BIO) group and 252.5 months (95%CI:202.1-not estimable) for those receiving endocrine therapy (ENDO) ± BIO, but was not-reached in patients undergoing CH + ENDO (p = 0.0305). Patients aged ≥ 55 years (HR 2.92, 95% CI 1.4–6.0), those with luminal B (HR 4.10, 95% CI 1.5–11.1), stage IV disease (HR 8.69, 95% CI 2.6–28.9) or axial + appendicular or other site of BM (HR:2.20, 95% CI 1.1–4.6) had a higher risk of death, while those with no pain at BM diagnosis (HR 0.49, 95% CI 0.2–0.9) and patients receiving ENDO ± BIO (HR:0.40, 95% CI 0.2–0.8) had a better prognosis considering multivariate Cox regression model (Supplementary Table 2).
OS from diagnosis of metastatic disease
The median OS for patients with metastatic disease (metOS) was 66.8 months (95% CI 52.1–79.2). The molecular profile of subtypes was an independent prognostic factors according to metOS. A multivariate Cox regression model confirmed a poorer prognosis for patients with luminal B subtype (HR 3.67, 95% CI 1.5–8.7) (Supplementary Table 2).
Progression-free survival
Disease progression occurred in 167 patients. Median progression-free survival (PFS) was 15.1 months (95% CI 12.6–18.4). With respect to first-line treatment, median PFS was 13.4 months (95% CI 10.0–16.6) in the CH ±BIO arm, 17.3 months (95% CI 12.0–23.6) in the ENDO ± BIO group and 32.0 months (95% CI 12.7-Not estimable) in CH + ENDO patients. None of analyzed prognostic factors were found as statistically significant in univariate analysis, even if a HR of 0.51 (95% CI 0.27–0.95) was observed for patients treated with CH + ENDO with respect to those given CH alone after the first diagnosis of metastasis (p = 0.0849) (Supplementary Fig. 3) in univariate analysis. No differences in terms of time to disease progression were seen between synchronous and metachronous BM, BOM vs. BVM, first-line treatment, number and type of BM, and presence of pain at diagnosis. The presence of SREs at diagnosis did not have an impact on disease progression (Supplementary Table 3).
Bone metastasis progression-free survival
Median BM PFS was 45.9 months (95% CI 30.8–63.0). Older patients had a higher risk for progression to bone (HR: 1.51, 95% CI 1.1–2.1) in univariate analysis (Supplementary Table 3).
Time to first SRE
Ninety-eight (44.5%) patients had at least one SRE during the course of their metastatic disease. Patients treated with zoledronic acid or pamidronate had a similar HR for SREs with respect to untreated patients (HR 1.32, 95% CI 0.74–2.38), while those taking denosumab had a HR of 0.20 (95% CI 0.04–0.87), indicating a reduced risk of SRE (Supplementary Fig. 4). Supplementary data are reported in Appendix 2.
Discussion
Bone metastases represent a common complication of cancer, their incidence reaching around 65% in BC2. There are still aspects of bone metastatic disease that need to be further investigated15,16.
As reported in previous studies, our case series showed a majority of lytic bone metastases17,18. The nature (lytic or not) of BM would not appear to impact patient outcome. Small BC tumors (T0–T2) were associated with metachronous BM, with a time to bone involvement of 65.1 months after the primary diagnosis of BC, indicating that the information collected also regarded patients with latent BM. This subgroup possesses the clinical phenotype of bone metastatic cells characterized by dormancy in which adjuvant BTT could prove useful to prevent BM formation19. The mOS from the diagnosis of distant disease (5.5 years) was similar to that reported in other studies, whereas mOS from the primary BC diagnosis differed20–22. Such findings reflect the good prognosis of the primary BC patients included in our study, representing a real-world population.
Recent studies on a population-based cancer registry and a National Cancer Database observed that patients aged < 60 years now show better survival than those reported in previous studies in which younger age and premenopausal status were associated with poorer survival22–24. Our study had similar findings, with improved mOS from the time of diagnosis of metastastic disease and primary BC in patients < 55 years and < 65 years, respectively.
Our data are also consistent with previous literature reporting that luminal BC subtype confers an independent survival benefit regardless of tumor receptor status25,26.
The initial stage of disease at BC diagnosis represented an important prognostic factor for survival and is consistent with the literature on this topic27,28. Some preclinical and clinical studies have reported promising results for concurrent ENDO + CH in postmenopausal patients with metastatic hormone-positive BC29,30. In line with these findings, our patients undergoing the ENDO + CH combination showed a slight benefit in terms of mPFS with respect to those treated with ENDO + CH ± BIO. These fascinating suggestions warrant further exploration and validation prospective clinical trials.
Previous studies have shown a better prognosis for BOM patients than for those with BVM. However, in our study BOM and BVM groups had a similar mOS which may be attributable to a conditioning effect of the molecular BC subtype and also to new treatments available.
A recently published study on BOM reported no correlation between bone pain and survival. Our results are in line with these findings in both BOM and BVM groups. BM localization proved to have a prognostic value in our case series, an appendicular site negatively impacting mOS more than axial or mixed localizations. In a retrospective study conducted by Parkes et al., BOM patients with axial localisation had a mOS from the diagnosis of distant disease of 5.62 years compared to 6.78 years for those with appendicular BM and 4.58 years the appendicular + axial BM group31. A possible explanation for this could be the higher incidence of axial bone metastases in luminal BC.
Another interesting finding of our study was that patients with single or oligo- metastases had a better prognosis than those with multiple bone lesions. Although there is already evidence of this for the former32, interest in oligo-metastatic disease has recently come to the fore because of its challenging management33,34.
It has been seen that changes in BC cell biology occur between primary tumors and metastases35,36. In our study a significant difference in PgR expression was observed between primary BC and metastatic bone lesions. Clinicians should take this into account in cases of disease recurrence more than 5 years after the primary diagnosis.
Age was found to have a significant impact on OS. This is in line with retrospective works published on BC and BM patients in which age was found to be an independent prognostic factor30.
Finally, our data confirm the protective effect of denosumab in preventing SREs, which leveled off over time. Albeit with an incidence reducing over time.
One of the limitations of our study is the patient sample even though it’s consistent with other studies in which patients were followed prospectively in a dedicated database on BM and not extrapolated from large registries28,32. Another limit is the lack of information available on specific treatments, a result of opting not to enter a large amount of data into the database. To overcome this we grouped treatments into specific categories.
In contrast, the strengths of our study are its collection of prospective data on BM and their clinical evolution and the fact that it constitutes a national representative study population for this disease setting.
In conclusion, the Italian BMDB represents an invaluable tool to better understand the natural history of bone metastases from breast cancer and improve their management. The Italian BMDB continues to enroll patients also in other solid tumors to increase the case series and give more answer to clinician questions.
Supplementary Information
Supplementary Information.
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Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-021-83749-1.
Acknowledgements
The authors thanks all the other members of Banca Dati Metastasi Ossee Study Team: Luigi Cavanna (A.O. Piacenza, Piacenza, Italy), Antonio Maestri (S. Maria della Scaletta Hospital, Imola, Bologna), Francesco Ferraù (Medical Oncology Division, San Vincenzo Hospital, Taormina, Italy), Maria Banzi (Medical Oncology Unit, Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy), Bruno Daniele (Gaetano Rummo Hospital, Benevento, Italy), Sergio Fava (Ospedale Civile di Legnano, Legnano, Italy), Gaetano Lanzetta (Medical Oncology Unit, Istituto Neurotramutologico Italiano, Grottaferrata, Italy). The authors thanks Gráinne Tierney and Cristiano Verna for editorial assistance.
Author contributions
Conception and design: A.B., T.I. and F.F. IT support: R.V. Provision of study materials or patients: A.B., T.I., F.F., M.F., M.R.F., F.A., R.B., E.C., G.P., F.S., N.R., L.G., S.D.B., G.D.M., V.F. and F.R. Data analysis and interpretation: A.B., T.I., F.F., M.R.F., F.A., M.F., R.B., G.P., F.S. and E.C. Manuscript writing and final approval of manuscript: All authors.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The datasets gathered and analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | DENOSUMAB | DrugsGivenReaction | CC BY | 33619285 | 18,321,151 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | First prospective data on breast cancer patients from the multicentre italian bone metastasis database.
Bone metastases (BM) are still the main cause of morbidity in cancer patients because of skeletal-related events (SREs) that reduce quality of life. They have also led to increased social and healthcare costs. At present, data available on BM are insufficient. This was a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 months' follow-up. Information on patients at the first diagnosis of BM, including demographics and characteristics of the primary tumor and BM. Data were periodically updated by participating centres and reviewed by the coordinator centre. From October 2014 to July 2019, 618 patients with BM from solid tumors were enrolled and 220 were eligible for the present study. Median age was 62 years (range 26-86). Median follow-up was 34 months (range 6-149). At the time of enrolment, 109 (50%) had only BM (BOM) and 109 (50%) had concomitant visceral lesions and BM (BVM). Median time-to-first BM was 47 months (range 0-312) in BOM and 78.6 months in BVM patients. Disease-free interval differed on the basis of BC molecular subtype and stage. Ninety-eight BM patients had at least on SRE. Zoledronate was used in 69.1% of cases and denosumab in 28.3%. First-line treatment was hormone-based (50.7%), chemotherapy-based (38.7%) or chemotherapy- + hormone therapy-based (9.7%). Median progression-free and overall survival were 15.1 months (95% CI 12.6-18.4) and 66.8 months (95% CI 52.1-79.2), respectively. Our prospective study could substantially help to better understand the natural history of BM from BC.
Introduction
Breast cancer (BC) is the most common malignancy and a major cause of morbidity and mortality among women. The mortality rate has decreased thanks to improved diagnostic procedures, screening and more advanced treatments. However, the rate of recurrence in distant organs is still fairly high, ranging from 20 to 30%1,2.
Bone is the most common site of metastasis in BC and significantly impacts patient survival3–5.
Bone metastases (BMs) represent an important clinical-epidemiological issue in oncology because their diagnosis and treatment are often necessarily handled by several specialists, resulting in fragmented patient information6. For these reasons, great efforts have been made to develop a new scientific and clinical branch of medicine, i.e. Osteoncology7.
The major problem faced by BM patients is the risk of skeletal complications defined as skeletal-related events (SREs) all of which are highly detrimental to quality of life and survival2,8,9.
There is still limited information available on BM clinical presentation, the difference in disease response between bone and visceral sites, and the difference in prognosis between solitary, oligometastatic and multiple sites or axial and trunk bone metastases10. A clearer understanding of their natural evolution would thus help us to identify new strategies capable of reducing both BM incidence and morbidity.
The risk of SREs in BC patients with BM has been the focus of numerous studies11–13. However, their findings are of limited value because of their poor generalizability with respect to current clinical practice. In the retrospective studies, authors usually considered a lengthy time period during which available therapies and clinical practice may have changed substantially. In the prospective studies, patients were followed for a short period (24 months) and data were extrapolated from a BC database rather than from a database dedicated to BM. Furthermore, in recent years, new therapeutic options have become available. There has also been growing interest in BM since dedicated multidisciplinary groups began to emerge14.
The main aims of this prospective multicenter study were to evaluate the evolution of skeletal disease in BC patients, assess the impact of BM on disease outcome, examine the role of a number of clinical-pathological parameters in predicting survival, and further our understanding of the natural history of patients with BM from BC.
Materials and methods
This was a multicentre prospective observational study of patients with BM from BC with at least 6 months follow-up, enrolled into the prospective Italian Bone Metastases Data Base (BMDB). The study was approved by the Local Ethics Committee of each participating centre and carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. List of participating centers was provided in Supplementary Table 1. Written informed consent was obtained from all patients. Information on data source is provided in Appendix 1.
Data extraction and measure definition
The evolution of skeletal disease in BC patients was evaluated by extracting data from the BMDB for patients who had a first diagnosis of BC with a synchronous (within 2 months) or metachronous diagnosis of bone metastasis and were followed up for at least 6 months after the BM diagnosis.
Time to event outcomes were defined as follows: disease-free interval (DFI) was the time from primary BC disease to the appearance of the first metastasis (bone or visceral), and bone disease-free interval (bDFI) was the time between diagnosis of primary BC and first diagnosis of BM. Overall survival (OS) was calculated as the time from the date of the diagnosis of primary BC to the date of death. OS from metastatic disease (metOS) was calculated as the time from the diagnosis of metastasis (either bone or visceral) to death. Progression-free survival (PFS) was the time between the date of the first diagnosis of bone metastasis and date of the first documented evidence of disease progression (bone or visceral) and death. Bone PFS (bPFS) was the time between the date of the first diagnosis of BM and first progression to bone and death. Time-to-first SRE was the time between the first diagnosis of BM and the first SRE event. Patients without events of interest were censored at the date of the last follow-up visit.
Statistical analysis
Descriptive statistics are used to summarize baseline patient characteristics, BM characteristics and treatment patterns. Continuous variables are presented using median and range or interquartile range. The Wilcoxon rank-sum test was used for continuous variables, together with the chi-squared test or Fisher’s exact test, as appropriate. McNemar’s test was used in cases of paired data. Time-to-event measures were analysed using the Kaplan–Meier method, and the nonparametric log-rank test was used to evaluate the role of stratification factor. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) and relative 95% confidence intervals (CI) of potential clinical prognostic factors for time-to-event outcomes.
All statistical analyses were performed using STATA/MP 15.0 for Windows (StataCorp LLP, College Station, TX, USA).
Results
Patient characteristics
From October 1st 2014 to June 30th 2018, 618 patients with BM from any solid tumor were registered in the Italian BMDB. Three hundred and nine had BC as the primary site of disease and 220/309 with at least 6 months’ follow up were included in the present analysis (Fig. 1). Median age was 62 (range 26–85) years.Figure 1 Study flow diagram.
At the time of the first diagnosis of BM, 152 (92.1%) patients showed a good ECOG PS (0–1). Forty-nine (22.3%) patients were diagnosed with BM synchronous to the primary tumor, while metachronous BM were found in 171 patients.
Bone-only metastases (BOM) were found in 109 (50.0%) patients, while the remaining 109 had concomitant visceral and BM (BVM). Histological and biological characteristics of the primary BC are shown in Tables 1 and 2. Luminal A and B tumors were more frequently associated with BOM, whereas basal-like or HER2-enriched BC subtypes more often showed BVM (p = 0.012). A higher, albeit not significant, Ki-67 value was observed for patients with BVM (p = 0.074). The majority of patients had T0-T2 (n = 159, 85%) and node-positive tumors (n = 138, 74.6%) at diagnosis (Table 3), the former associated with a higher rate of metachronous BM than synchronous BM (83.2% and 16.8%, respectively) (p < 0.001) (Table 4). Patients with N0 primary tumors had a higher incidence of metachronous BM than synchronous (95.8% and 4.2%, respectively) (p = 0.001). No difference between BOM or BVM according to node status (node negative vs. node positive tumors) was observed. Both node-negative and node-positive patients showed a high rate of metachronous BM (95.8% and 75.5%, respectively), even if in node-negative patients there is a significantly higher proportion of patients with metachronous BM.Table 1 Patient characteristics at baseline and at onset of BM.
Patients (n = 220)
Median age, years (range) 62 (26–85)
No. (%)
Age at diagnosis of primary BM, years
< 65 133 (60.5)
65 87 (69.5)
ECOG PS at diagnosis of primary BM
0–1 152 (92.1)
≥ 2 13 (7.9)
Unknown 55
Histology
Ductal carcinoma 166 (75.5)
Lobular carcinoma 29 (13.0)
Mixed ductal and lobular carcinoma 11 (5.0)
Adenocarcinoma, NOS 9 (4.0)
Signet ring cell carcinoma 1 (0.5)
Other 4 (2.0)
pT at primary diagnosis of BC
T0–T2 159 (85.0)
T3–T4 28 (15.0)
Tx 31
pN at primary diagnosis of BC
N0 47 (25.4)
N+ 138 (74.6)
Nx 33
Stage at diagnosis of primary disease
I 28 (14.1)
II 68 (34.3)
III 42 (21.2)
IV 60 (30.3)
Unknown 22
BC molecular subtype
Luminal A 35 (18.8)
Luminal B 118 (63.4)
Basal-like 8 (4.3)
HER+ 25 (13.4)
Unknown 34
Grading
G1 6 (3.7)
G2 85 (52.5)
G3 71 (43.8)
Unknown 58
Bone metastasis
Synchronous 49 (22.3)
Metachronous 171 (77.7)
BOM 109 (50.0)
BVM 109 (50.0)
BM bone metastasis, ECOG PS Eastern Cooperative Oncology Group Performance Status, NOS not otherwise specified, BC breast cancer, pT primary tumour, pN pathological lymph node, Nx unknown lymph node stage, G grade, BOM bone-only metastasis, BVM visceral and bone metastasis.
Table 2 Biomarker characteristics at diagnosis of primary BC and at onset of BM.
BC characteristics At diagnosis At the onset of bone metastasis
Positive* (%) Negative* (%) NA Positive* (%) Negative* (%) NA
ER 183 (89.7) 21 (10.3) 16 48 (88.9) 6 (11.1) 166
PgR 144 (70.6) 60 (29.4) 16 24 (45.3) 29 (54.7) 167
< 15% ≥ 15% NA < 15% ≥ 15% NA
Ki-67 145 (79.7) 37 (20.3) 38 29 (65.9) 15 (34.1) 176
Positive/(+ + +) Negative/0–2 + NA Positive/(+ + +) Negative/0–2 + NA
HER2 (IHC or FISH) 24 (12.9) 162 (87.1) 34 7 (13.7) 44 (86.3) 169
BC breast cancer, BM bone metastasis, ER oestrogen receptor, PgR progesterone receptor, NA not available, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
*For ER and PgR, positive if ≥ 10%, negative if < 10%.
Table 3 Baseline patient characteristics in relation to presence of visceral metastases.
Baseline BC characteristics No. patients
(n = 218) BOM (n = 109)
No. (%) BVM (n = 109)
No. (%) p-value
Age at diagnosis of bone metastasis, years
< 65 108 (49.1) 70 (53.0) 62 (47.0) 0.268
≥ 65 112 (50.9) 39 (45.3) 47 (54.7)
pT at primary diagnosis of breast cancer
T0–T2 159 (85.0) 84 (52.8) 75 (47.2) 0.531
T3–T4 28 (15.0) 13 (46.4) 15 (53.6)
pN at primary diagnosis of breast cancer
N0 47 (25.4) 26 (55.3) 21 (44.7) 0.330
N+ 138 (74.6) 65 (47.1) 73 (52.9)
Stage at diagnosis of primary disease
I 27 (13.8) 16 (59.3) 11 (40.7) 0.621
II 67 (34.2) 31 (46.3) 36 (53.7)
III 42 (21.4) 23 (54.8) 19 (45.2)
IV 60 (30.6) 33 (55.0) 27 (45.0)
Unknown 22 6 16
Breast cancer molecular subtype
Luminal A 35 (19.0) 26 (74.3) 9 (25.7) 0.012
Luminal B 118 (64.1) 60 (50.8) 58 (49.2)
Basal-like 7 (3.8) 2 (28.6) 5 (71.4)
HER+ 24 (13.1) 9 (37.5) 15 (62.5)
Unknown 34 12 22
Median Ki67% (interquartile range) 20 (10–31) 16 (8–30) 20 (10–35) 0.074
ER
Negative 19 (9.4) 6 (31.6) 13 (68.4) 0.075
Positive 183 (90.6) 97 (53.1) 86 (46.9)
Unknown or not performed 16 6 10
PgR
Negative 58 (28.7) 29 (50.0) 29 (50.0) 0.858
Positive 144 (71.3) 74 (51.4) 70 (48.6)
Unknown or not performed 16 6 10
HER2 (IHC or FISH)
Negative 161 (87.5) 89 (55.3) 72 (44.7) 0.066
Positive 23 (12.5) 8 (34.8) 15 (65.2)
Unknown or not performed 34 12 22
Adjuvant therapy
No 73 (33.4) 35 (47.9) 38 (52.1) 0.632
Yes 144 (66.1) 74 (51.4) 70 (48.6)
Neoadjuvant therapy
No 196 (91.2) 97 (49.5) 99 (50.5) 0.484
Yes 19 (8.8) 11 (57.9) 8 (42.1)
BC breast cancer, BOM bone-only metastasis, BVM visceral and bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
Table 4 Baseline patient characteristics in relation to synchronous or metachronous metastases.
Baseline BC characteristics No. patients
(n = 220) Synchronous BM
(n = 49)
No. (%) Metachronous BM
(n = 171)
No. (%) p-value
Age at diagnosis of bone metastasis, years
< 65 133 (49.1) 32 (24.1) 101 (75.9) 0.431
≥ 65 87 (50.9) 17 (19.5) 70 (80.5)
pT at primary diagnosis of breast cancer
T0–T2 161 (85.0) 27 (16.8) 134 (83.2) < 0.001
T3–T4 28 (15.0) 15 (53.6) 13 (46.4)
pN at primary diagnosis of breast cancer
N0 48 (25.6) 2 (4.2) 46 (95.8) 0.001
N+ 137 (74.3) 34 (24.5) 105 (75.5)
Stage at diagnosis of primary disease
I 28 (14.1) 0 (0.0) 28 (100.0) –
II 68 (34.4) 0 (0.0) 68 (100.0)
III 42 (21.2) 0 (0.0) 42 (100.0)
IV 60 (30.3) 49 (81.7) 11 (18.3)
Unknown 22 – 22
Breast cancer molecular subtype
Luminal A 35 (18.8) 7 (20.0) 28 (80.0) 0.315
Luminal B 118 (63.4) 31 (26.3) 87 (73.7)
Basal-like 8 (4.3) 1 (12.5) 7 (87.5)
HER+ 25 (13.4) 10 (40.0) 15 (60.0)
Unknown 34 – 34
Median Ki67% (interquartile range) 20 (10–31) 23 (15–35) 16 (10–30) 0.087
ER
Negative 21 (9.9) 2 (9.5) 19 (90.5) 0.114
Positive 183 (90.1) 47 (25.7) 136 (74.3)
Unknown or not performed 16 – 16
PgR
Negative 60 (29.4) 11 (18.3) 49 (81.7) 0.220
Positive 144 (70.6) 38 (26.4) 106 (73.6)
Unknown or not performed 16 – 16
HER2 (IHC or FISH)
Negative 162 (87.1) 38 (23.5) 124 (76.5) 0.057
Positive 24 (12.9) 10 (41.7) 14 (58.3)
Unknown or not performed 34 1 33
BM bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
Bone biopsy was performed in 58 (26.4%) cases. The median time from primary disease diagnosis to the appearance of BM in this subgroup was 79 months (95%CI: 65.0–118.1).
Time to event outcomes
Disease-free interval
Disease free-interval was calculated excluding patients with synchronous disease at bone (n = 49) and visceral (n = 2). The disease-free interval (DFI) differed slightly according to molecular subtype. The univariate hazard ratio (HR) for visceral or bone metastasis was higher in luminal B tumors (1.66, 95% confidence interval [CI] 1.1–2.5) (p = 0.023), basal-like tumors (3.92, 95% CI 1.6–9.7) (p = 0.003), and HER2-enriched tumors (1.28, 95% CI 0.7–2.4) (p = 0.442).
DFI for patients with stage I disease at diagnosis of primary BC was longer than that for stage III patients (median 67.2 months, 95% CI 53.1–96.1, vs. 58.1 months, 95% CI 41.9–73.4), with a univariate HR of 1.84 (95% CI 1.1–3.0) (p = 0.015) for the stage III group, and 0.98 (95% CI 0.6–1.5) (p = 0.931) for the stage II group. Older patients had a higher risk of metastasis (HR 1.91, 95% CI 1.4–2.7), as did those with larger tumors at diagnosis (HR: 3.7, 95% CI 1.9–7.1). Multivariate analysis confirmed these data for patients with basal-like and larger tumors (Table 5).Table 5 Median DFI and independent risk factors for metastasis.
Overall DFI bDFI
Median
(95%CI) HR from univariate Cox regression model (95%CI) HR from multivariate Cox regression model (95%CI) Median
(95%CI) HR from univariate Cox regression model (95%CI) HR from multivariate Cox regression model (95%CI)
All cases 75.7 (63.5–87.3) – – 78.2 (63.6–87.9) – –
Age at diagnosis of primary BC, years
< 55 82.1 (65.4–112.9) 1.00 1.00 89.6 (65.4–114.8) 1.00 1.00
≥ 55 65.0 (48.1–81.5) 1.91 (1.4–2.7) 1.48 (0.9–2.2) 65.0 (51.1–86.0) 1.89 (1.4–2.6) 1.27 (0.9–1.9)
BC molecular subtypes
Luminal A 101.9 (57.0–125.7) 1.00 1.00 101.9 (57.0–125.7) 1.00 1.00
Luminal B 63.5 (48.6–75.7) 1.66 (1.1–2.5) 1.46 (0.9–2.4) 63.6 (52.7–78.5) 1.54 (0.9–2.4) 1.27 (0.8–2.0)
Basal-like 30.0 (13.4–NE) 3.92 (1.6–9.7) 3.94 (1.4–11.0) 30.0 (2.1–66.1) 4.29 (1.8–10.1) 3.82 (1.4–10.6)
HER2+ 53.1 (30.9–100.1) 1.28 (0.7–2.4) 1.44 (0.7–2.9) 53.1 (47.9–100.2) 1.17 (0.6–2.2) 1.22 (0.6–2.5)
Stage at diagnosis
I 67.2 (53.1–96.1) 1.00 1.00 82.2 (53.6–125.7) 1.00 1.00
II 83.3 (66.5–99.2) 0.98 (0.6–1.5) 1.09 (0.5–2.3) 83.2 (66.5–101.9) 1.07 (0.7–1.7) 1.16 (0.6–2.4)
III 58.1 (41.9–73.4) 1.84 (1.1–3.0) 1.35 (0.5–3.2) 60.9 (41.9–75.6) 2.1 (1.3–3.5) 1.55 (0.7–3.7)
IV – – – – – –
pT at primary diagnosis of BC
T0–T2 76.7 (61.0–87.3) 1.00 1.00 78.5 (63.6–87.9) 1.00 1.00
T3–T4 20.6 (3.3–65.4) 3.7 (1.9–7.1) 3.24 (1.5–7.1) 18.6 (3.3–57.0) 4.5 (2.4–8.2) 3.02 (1.4–6.6)
pN at primary diagnosis of BC
N0 83.3 (56.1–101.9) 1.00 1.00 89.6 (61.1–118.2) 1.00 1.00
N+ 66.5 (56.3–80.0) 1.36 (0.9–1.9) 0.91 (0.5–1.7) 66.5 (57.0–79.0) 1.47 (1.0–2.1) 0.97 (0.5–1.8)
DFI disease-free interval, bDFI bone disease-free interval, HR hazard ratio, BC breast cancer, NE not evaluable from statistical software, pT primary tumour, pN pathological lymph node.
Bone disease-free interval
For this analysis, were excluded all patients with synchronous bone metastasis (n = 49). Median time to BM appearance was 78.2 months (95% confidence interval [CI] 63.6–87.9) for all patients.
Median bone disease-free interval (bDFI) was 63.5 months (95% CI 47.9–83.3) for the BM-only group at diagnosis and 86.6 months (95% CI 66.5–99.6) for those with visceral metastases. Median bDFI was 78.5 months (95% CI 63.6–87.9) in T0–T2 patients and 18.6 months (95% CI 3.3–57.0) in the T3–T4 group (p ≤ 0.001). The group with node-negative BC had a median bDFI of 8.6 months (95% CI 61.1–118.2) compared to 66.5 months (95% CI 57.0–79.0) for the node-positive subgroup (log rank test p = 0.032) (Fig. 2a,b). bDFI was significantly higher (p < 0.001) in patients aged < 55 years at diagnosis than in those ≥ 55 years, (median 89.6 [95% CI 65.4–114.8] vs. 65.0 [95% CI 51.1–86.0] months) (Supplementary Fig. 1). Multivariate analyses confirmed a higher risk for patients with basal-like and larger tumors (Table 5).Figure 2 Disease-free interval by (a) T and (b) N of primary disease.
Overall survival
Median follow-up was 46 months (range: 6–117) on 220 evaluable patients.
Seventy-four deaths were observed during follow-up. Median OS was 217.5 months (95% CI 172.5–340.1).
Molecular profile subtypes were an independent prognostic factor. Median OS (mOS) in patients with luminal A tumors was not-reached and 128.1 months (95% CI 108.0–182.6) for those with luminal B tumors, 101.2 months (95% CI 17.1–not estimable) for patients with basal-like BC, and 274.5 months (95% CI 70.3-–not estimable) for those HER2-enriched BC (p = 0.010). Patients aged ≥ 55 years and those with stage IV disease at diagnosis had a shorter mOS (128.1 months [95% CI 101.2–182.6] and 65.3 months [95% CI 41.0–80.9], respectively) than the groups diagnosed at a younger age (< 55 years) and with lower-stage disease (Supplementary Fig. 2a,b). Patients with pain at the first diagnosis of bone metastases had an mOS of 143.8 months (95% CI 98.0–247.5) with respect to 257.4 months (95% CI 135.1–not estimable) for those with no pain. mOS of the group with axial BM was 252.5 months (95% CI 182.5–343.0), 157.6 months (95% CI41.0–Not estimable) for those with appendicular BM, and 217.5 months (95% CI 100.9–Not estimable) for patients with both types of metastases (p = 0.009).
mOS of patients undergoing first-line treatment was 135.1 months (95% CI 102.9–257.4) for the chemotherapy (CH) ± biological therapy (BIO) group and 252.5 months (95%CI:202.1-not estimable) for those receiving endocrine therapy (ENDO) ± BIO, but was not-reached in patients undergoing CH + ENDO (p = 0.0305). Patients aged ≥ 55 years (HR 2.92, 95% CI 1.4–6.0), those with luminal B (HR 4.10, 95% CI 1.5–11.1), stage IV disease (HR 8.69, 95% CI 2.6–28.9) or axial + appendicular or other site of BM (HR:2.20, 95% CI 1.1–4.6) had a higher risk of death, while those with no pain at BM diagnosis (HR 0.49, 95% CI 0.2–0.9) and patients receiving ENDO ± BIO (HR:0.40, 95% CI 0.2–0.8) had a better prognosis considering multivariate Cox regression model (Supplementary Table 2).
OS from diagnosis of metastatic disease
The median OS for patients with metastatic disease (metOS) was 66.8 months (95% CI 52.1–79.2). The molecular profile of subtypes was an independent prognostic factors according to metOS. A multivariate Cox regression model confirmed a poorer prognosis for patients with luminal B subtype (HR 3.67, 95% CI 1.5–8.7) (Supplementary Table 2).
Progression-free survival
Disease progression occurred in 167 patients. Median progression-free survival (PFS) was 15.1 months (95% CI 12.6–18.4). With respect to first-line treatment, median PFS was 13.4 months (95% CI 10.0–16.6) in the CH ±BIO arm, 17.3 months (95% CI 12.0–23.6) in the ENDO ± BIO group and 32.0 months (95% CI 12.7-Not estimable) in CH + ENDO patients. None of analyzed prognostic factors were found as statistically significant in univariate analysis, even if a HR of 0.51 (95% CI 0.27–0.95) was observed for patients treated with CH + ENDO with respect to those given CH alone after the first diagnosis of metastasis (p = 0.0849) (Supplementary Fig. 3) in univariate analysis. No differences in terms of time to disease progression were seen between synchronous and metachronous BM, BOM vs. BVM, first-line treatment, number and type of BM, and presence of pain at diagnosis. The presence of SREs at diagnosis did not have an impact on disease progression (Supplementary Table 3).
Bone metastasis progression-free survival
Median BM PFS was 45.9 months (95% CI 30.8–63.0). Older patients had a higher risk for progression to bone (HR: 1.51, 95% CI 1.1–2.1) in univariate analysis (Supplementary Table 3).
Time to first SRE
Ninety-eight (44.5%) patients had at least one SRE during the course of their metastatic disease. Patients treated with zoledronic acid or pamidronate had a similar HR for SREs with respect to untreated patients (HR 1.32, 95% CI 0.74–2.38), while those taking denosumab had a HR of 0.20 (95% CI 0.04–0.87), indicating a reduced risk of SRE (Supplementary Fig. 4). Supplementary data are reported in Appendix 2.
Discussion
Bone metastases represent a common complication of cancer, their incidence reaching around 65% in BC2. There are still aspects of bone metastatic disease that need to be further investigated15,16.
As reported in previous studies, our case series showed a majority of lytic bone metastases17,18. The nature (lytic or not) of BM would not appear to impact patient outcome. Small BC tumors (T0–T2) were associated with metachronous BM, with a time to bone involvement of 65.1 months after the primary diagnosis of BC, indicating that the information collected also regarded patients with latent BM. This subgroup possesses the clinical phenotype of bone metastatic cells characterized by dormancy in which adjuvant BTT could prove useful to prevent BM formation19. The mOS from the diagnosis of distant disease (5.5 years) was similar to that reported in other studies, whereas mOS from the primary BC diagnosis differed20–22. Such findings reflect the good prognosis of the primary BC patients included in our study, representing a real-world population.
Recent studies on a population-based cancer registry and a National Cancer Database observed that patients aged < 60 years now show better survival than those reported in previous studies in which younger age and premenopausal status were associated with poorer survival22–24. Our study had similar findings, with improved mOS from the time of diagnosis of metastastic disease and primary BC in patients < 55 years and < 65 years, respectively.
Our data are also consistent with previous literature reporting that luminal BC subtype confers an independent survival benefit regardless of tumor receptor status25,26.
The initial stage of disease at BC diagnosis represented an important prognostic factor for survival and is consistent with the literature on this topic27,28. Some preclinical and clinical studies have reported promising results for concurrent ENDO + CH in postmenopausal patients with metastatic hormone-positive BC29,30. In line with these findings, our patients undergoing the ENDO + CH combination showed a slight benefit in terms of mPFS with respect to those treated with ENDO + CH ± BIO. These fascinating suggestions warrant further exploration and validation prospective clinical trials.
Previous studies have shown a better prognosis for BOM patients than for those with BVM. However, in our study BOM and BVM groups had a similar mOS which may be attributable to a conditioning effect of the molecular BC subtype and also to new treatments available.
A recently published study on BOM reported no correlation between bone pain and survival. Our results are in line with these findings in both BOM and BVM groups. BM localization proved to have a prognostic value in our case series, an appendicular site negatively impacting mOS more than axial or mixed localizations. In a retrospective study conducted by Parkes et al., BOM patients with axial localisation had a mOS from the diagnosis of distant disease of 5.62 years compared to 6.78 years for those with appendicular BM and 4.58 years the appendicular + axial BM group31. A possible explanation for this could be the higher incidence of axial bone metastases in luminal BC.
Another interesting finding of our study was that patients with single or oligo- metastases had a better prognosis than those with multiple bone lesions. Although there is already evidence of this for the former32, interest in oligo-metastatic disease has recently come to the fore because of its challenging management33,34.
It has been seen that changes in BC cell biology occur between primary tumors and metastases35,36. In our study a significant difference in PgR expression was observed between primary BC and metastatic bone lesions. Clinicians should take this into account in cases of disease recurrence more than 5 years after the primary diagnosis.
Age was found to have a significant impact on OS. This is in line with retrospective works published on BC and BM patients in which age was found to be an independent prognostic factor30.
Finally, our data confirm the protective effect of denosumab in preventing SREs, which leveled off over time. Albeit with an incidence reducing over time.
One of the limitations of our study is the patient sample even though it’s consistent with other studies in which patients were followed prospectively in a dedicated database on BM and not extrapolated from large registries28,32. Another limit is the lack of information available on specific treatments, a result of opting not to enter a large amount of data into the database. To overcome this we grouped treatments into specific categories.
In contrast, the strengths of our study are its collection of prospective data on BM and their clinical evolution and the fact that it constitutes a national representative study population for this disease setting.
In conclusion, the Italian BMDB represents an invaluable tool to better understand the natural history of bone metastases from breast cancer and improve their management. The Italian BMDB continues to enroll patients also in other solid tumors to increase the case series and give more answer to clinician questions.
Supplementary Information
Supplementary Information.
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Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-021-83749-1.
Acknowledgements
The authors thanks all the other members of Banca Dati Metastasi Ossee Study Team: Luigi Cavanna (A.O. Piacenza, Piacenza, Italy), Antonio Maestri (S. Maria della Scaletta Hospital, Imola, Bologna), Francesco Ferraù (Medical Oncology Division, San Vincenzo Hospital, Taormina, Italy), Maria Banzi (Medical Oncology Unit, Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy), Bruno Daniele (Gaetano Rummo Hospital, Benevento, Italy), Sergio Fava (Ospedale Civile di Legnano, Legnano, Italy), Gaetano Lanzetta (Medical Oncology Unit, Istituto Neurotramutologico Italiano, Grottaferrata, Italy). The authors thanks Gráinne Tierney and Cristiano Verna for editorial assistance.
Author contributions
Conception and design: A.B., T.I. and F.F. IT support: R.V. Provision of study materials or patients: A.B., T.I., F.F., M.F., M.R.F., F.A., R.B., E.C., G.P., F.S., N.R., L.G., S.D.B., G.D.M., V.F. and F.R. Data analysis and interpretation: A.B., T.I., F.F., M.R.F., F.A., M.F., R.B., G.P., F.S. and E.C. Manuscript writing and final approval of manuscript: All authors.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The datasets gathered and analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | DENOSUMAB | DrugsGivenReaction | CC BY | 33619285 | 18,321,151 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to bone'. | First prospective data on breast cancer patients from the multicentre italian bone metastasis database.
Bone metastases (BM) are still the main cause of morbidity in cancer patients because of skeletal-related events (SREs) that reduce quality of life. They have also led to increased social and healthcare costs. At present, data available on BM are insufficient. This was a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 months' follow-up. Information on patients at the first diagnosis of BM, including demographics and characteristics of the primary tumor and BM. Data were periodically updated by participating centres and reviewed by the coordinator centre. From October 2014 to July 2019, 618 patients with BM from solid tumors were enrolled and 220 were eligible for the present study. Median age was 62 years (range 26-86). Median follow-up was 34 months (range 6-149). At the time of enrolment, 109 (50%) had only BM (BOM) and 109 (50%) had concomitant visceral lesions and BM (BVM). Median time-to-first BM was 47 months (range 0-312) in BOM and 78.6 months in BVM patients. Disease-free interval differed on the basis of BC molecular subtype and stage. Ninety-eight BM patients had at least on SRE. Zoledronate was used in 69.1% of cases and denosumab in 28.3%. First-line treatment was hormone-based (50.7%), chemotherapy-based (38.7%) or chemotherapy- + hormone therapy-based (9.7%). Median progression-free and overall survival were 15.1 months (95% CI 12.6-18.4) and 66.8 months (95% CI 52.1-79.2), respectively. Our prospective study could substantially help to better understand the natural history of BM from BC.
Introduction
Breast cancer (BC) is the most common malignancy and a major cause of morbidity and mortality among women. The mortality rate has decreased thanks to improved diagnostic procedures, screening and more advanced treatments. However, the rate of recurrence in distant organs is still fairly high, ranging from 20 to 30%1,2.
Bone is the most common site of metastasis in BC and significantly impacts patient survival3–5.
Bone metastases (BMs) represent an important clinical-epidemiological issue in oncology because their diagnosis and treatment are often necessarily handled by several specialists, resulting in fragmented patient information6. For these reasons, great efforts have been made to develop a new scientific and clinical branch of medicine, i.e. Osteoncology7.
The major problem faced by BM patients is the risk of skeletal complications defined as skeletal-related events (SREs) all of which are highly detrimental to quality of life and survival2,8,9.
There is still limited information available on BM clinical presentation, the difference in disease response between bone and visceral sites, and the difference in prognosis between solitary, oligometastatic and multiple sites or axial and trunk bone metastases10. A clearer understanding of their natural evolution would thus help us to identify new strategies capable of reducing both BM incidence and morbidity.
The risk of SREs in BC patients with BM has been the focus of numerous studies11–13. However, their findings are of limited value because of their poor generalizability with respect to current clinical practice. In the retrospective studies, authors usually considered a lengthy time period during which available therapies and clinical practice may have changed substantially. In the prospective studies, patients were followed for a short period (24 months) and data were extrapolated from a BC database rather than from a database dedicated to BM. Furthermore, in recent years, new therapeutic options have become available. There has also been growing interest in BM since dedicated multidisciplinary groups began to emerge14.
The main aims of this prospective multicenter study were to evaluate the evolution of skeletal disease in BC patients, assess the impact of BM on disease outcome, examine the role of a number of clinical-pathological parameters in predicting survival, and further our understanding of the natural history of patients with BM from BC.
Materials and methods
This was a multicentre prospective observational study of patients with BM from BC with at least 6 months follow-up, enrolled into the prospective Italian Bone Metastases Data Base (BMDB). The study was approved by the Local Ethics Committee of each participating centre and carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. List of participating centers was provided in Supplementary Table 1. Written informed consent was obtained from all patients. Information on data source is provided in Appendix 1.
Data extraction and measure definition
The evolution of skeletal disease in BC patients was evaluated by extracting data from the BMDB for patients who had a first diagnosis of BC with a synchronous (within 2 months) or metachronous diagnosis of bone metastasis and were followed up for at least 6 months after the BM diagnosis.
Time to event outcomes were defined as follows: disease-free interval (DFI) was the time from primary BC disease to the appearance of the first metastasis (bone or visceral), and bone disease-free interval (bDFI) was the time between diagnosis of primary BC and first diagnosis of BM. Overall survival (OS) was calculated as the time from the date of the diagnosis of primary BC to the date of death. OS from metastatic disease (metOS) was calculated as the time from the diagnosis of metastasis (either bone or visceral) to death. Progression-free survival (PFS) was the time between the date of the first diagnosis of bone metastasis and date of the first documented evidence of disease progression (bone or visceral) and death. Bone PFS (bPFS) was the time between the date of the first diagnosis of BM and first progression to bone and death. Time-to-first SRE was the time between the first diagnosis of BM and the first SRE event. Patients without events of interest were censored at the date of the last follow-up visit.
Statistical analysis
Descriptive statistics are used to summarize baseline patient characteristics, BM characteristics and treatment patterns. Continuous variables are presented using median and range or interquartile range. The Wilcoxon rank-sum test was used for continuous variables, together with the chi-squared test or Fisher’s exact test, as appropriate. McNemar’s test was used in cases of paired data. Time-to-event measures were analysed using the Kaplan–Meier method, and the nonparametric log-rank test was used to evaluate the role of stratification factor. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) and relative 95% confidence intervals (CI) of potential clinical prognostic factors for time-to-event outcomes.
All statistical analyses were performed using STATA/MP 15.0 for Windows (StataCorp LLP, College Station, TX, USA).
Results
Patient characteristics
From October 1st 2014 to June 30th 2018, 618 patients with BM from any solid tumor were registered in the Italian BMDB. Three hundred and nine had BC as the primary site of disease and 220/309 with at least 6 months’ follow up were included in the present analysis (Fig. 1). Median age was 62 (range 26–85) years.Figure 1 Study flow diagram.
At the time of the first diagnosis of BM, 152 (92.1%) patients showed a good ECOG PS (0–1). Forty-nine (22.3%) patients were diagnosed with BM synchronous to the primary tumor, while metachronous BM were found in 171 patients.
Bone-only metastases (BOM) were found in 109 (50.0%) patients, while the remaining 109 had concomitant visceral and BM (BVM). Histological and biological characteristics of the primary BC are shown in Tables 1 and 2. Luminal A and B tumors were more frequently associated with BOM, whereas basal-like or HER2-enriched BC subtypes more often showed BVM (p = 0.012). A higher, albeit not significant, Ki-67 value was observed for patients with BVM (p = 0.074). The majority of patients had T0-T2 (n = 159, 85%) and node-positive tumors (n = 138, 74.6%) at diagnosis (Table 3), the former associated with a higher rate of metachronous BM than synchronous BM (83.2% and 16.8%, respectively) (p < 0.001) (Table 4). Patients with N0 primary tumors had a higher incidence of metachronous BM than synchronous (95.8% and 4.2%, respectively) (p = 0.001). No difference between BOM or BVM according to node status (node negative vs. node positive tumors) was observed. Both node-negative and node-positive patients showed a high rate of metachronous BM (95.8% and 75.5%, respectively), even if in node-negative patients there is a significantly higher proportion of patients with metachronous BM.Table 1 Patient characteristics at baseline and at onset of BM.
Patients (n = 220)
Median age, years (range) 62 (26–85)
No. (%)
Age at diagnosis of primary BM, years
< 65 133 (60.5)
65 87 (69.5)
ECOG PS at diagnosis of primary BM
0–1 152 (92.1)
≥ 2 13 (7.9)
Unknown 55
Histology
Ductal carcinoma 166 (75.5)
Lobular carcinoma 29 (13.0)
Mixed ductal and lobular carcinoma 11 (5.0)
Adenocarcinoma, NOS 9 (4.0)
Signet ring cell carcinoma 1 (0.5)
Other 4 (2.0)
pT at primary diagnosis of BC
T0–T2 159 (85.0)
T3–T4 28 (15.0)
Tx 31
pN at primary diagnosis of BC
N0 47 (25.4)
N+ 138 (74.6)
Nx 33
Stage at diagnosis of primary disease
I 28 (14.1)
II 68 (34.3)
III 42 (21.2)
IV 60 (30.3)
Unknown 22
BC molecular subtype
Luminal A 35 (18.8)
Luminal B 118 (63.4)
Basal-like 8 (4.3)
HER+ 25 (13.4)
Unknown 34
Grading
G1 6 (3.7)
G2 85 (52.5)
G3 71 (43.8)
Unknown 58
Bone metastasis
Synchronous 49 (22.3)
Metachronous 171 (77.7)
BOM 109 (50.0)
BVM 109 (50.0)
BM bone metastasis, ECOG PS Eastern Cooperative Oncology Group Performance Status, NOS not otherwise specified, BC breast cancer, pT primary tumour, pN pathological lymph node, Nx unknown lymph node stage, G grade, BOM bone-only metastasis, BVM visceral and bone metastasis.
Table 2 Biomarker characteristics at diagnosis of primary BC and at onset of BM.
BC characteristics At diagnosis At the onset of bone metastasis
Positive* (%) Negative* (%) NA Positive* (%) Negative* (%) NA
ER 183 (89.7) 21 (10.3) 16 48 (88.9) 6 (11.1) 166
PgR 144 (70.6) 60 (29.4) 16 24 (45.3) 29 (54.7) 167
< 15% ≥ 15% NA < 15% ≥ 15% NA
Ki-67 145 (79.7) 37 (20.3) 38 29 (65.9) 15 (34.1) 176
Positive/(+ + +) Negative/0–2 + NA Positive/(+ + +) Negative/0–2 + NA
HER2 (IHC or FISH) 24 (12.9) 162 (87.1) 34 7 (13.7) 44 (86.3) 169
BC breast cancer, BM bone metastasis, ER oestrogen receptor, PgR progesterone receptor, NA not available, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
*For ER and PgR, positive if ≥ 10%, negative if < 10%.
Table 3 Baseline patient characteristics in relation to presence of visceral metastases.
Baseline BC characteristics No. patients
(n = 218) BOM (n = 109)
No. (%) BVM (n = 109)
No. (%) p-value
Age at diagnosis of bone metastasis, years
< 65 108 (49.1) 70 (53.0) 62 (47.0) 0.268
≥ 65 112 (50.9) 39 (45.3) 47 (54.7)
pT at primary diagnosis of breast cancer
T0–T2 159 (85.0) 84 (52.8) 75 (47.2) 0.531
T3–T4 28 (15.0) 13 (46.4) 15 (53.6)
pN at primary diagnosis of breast cancer
N0 47 (25.4) 26 (55.3) 21 (44.7) 0.330
N+ 138 (74.6) 65 (47.1) 73 (52.9)
Stage at diagnosis of primary disease
I 27 (13.8) 16 (59.3) 11 (40.7) 0.621
II 67 (34.2) 31 (46.3) 36 (53.7)
III 42 (21.4) 23 (54.8) 19 (45.2)
IV 60 (30.6) 33 (55.0) 27 (45.0)
Unknown 22 6 16
Breast cancer molecular subtype
Luminal A 35 (19.0) 26 (74.3) 9 (25.7) 0.012
Luminal B 118 (64.1) 60 (50.8) 58 (49.2)
Basal-like 7 (3.8) 2 (28.6) 5 (71.4)
HER+ 24 (13.1) 9 (37.5) 15 (62.5)
Unknown 34 12 22
Median Ki67% (interquartile range) 20 (10–31) 16 (8–30) 20 (10–35) 0.074
ER
Negative 19 (9.4) 6 (31.6) 13 (68.4) 0.075
Positive 183 (90.6) 97 (53.1) 86 (46.9)
Unknown or not performed 16 6 10
PgR
Negative 58 (28.7) 29 (50.0) 29 (50.0) 0.858
Positive 144 (71.3) 74 (51.4) 70 (48.6)
Unknown or not performed 16 6 10
HER2 (IHC or FISH)
Negative 161 (87.5) 89 (55.3) 72 (44.7) 0.066
Positive 23 (12.5) 8 (34.8) 15 (65.2)
Unknown or not performed 34 12 22
Adjuvant therapy
No 73 (33.4) 35 (47.9) 38 (52.1) 0.632
Yes 144 (66.1) 74 (51.4) 70 (48.6)
Neoadjuvant therapy
No 196 (91.2) 97 (49.5) 99 (50.5) 0.484
Yes 19 (8.8) 11 (57.9) 8 (42.1)
BC breast cancer, BOM bone-only metastasis, BVM visceral and bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
Table 4 Baseline patient characteristics in relation to synchronous or metachronous metastases.
Baseline BC characteristics No. patients
(n = 220) Synchronous BM
(n = 49)
No. (%) Metachronous BM
(n = 171)
No. (%) p-value
Age at diagnosis of bone metastasis, years
< 65 133 (49.1) 32 (24.1) 101 (75.9) 0.431
≥ 65 87 (50.9) 17 (19.5) 70 (80.5)
pT at primary diagnosis of breast cancer
T0–T2 161 (85.0) 27 (16.8) 134 (83.2) < 0.001
T3–T4 28 (15.0) 15 (53.6) 13 (46.4)
pN at primary diagnosis of breast cancer
N0 48 (25.6) 2 (4.2) 46 (95.8) 0.001
N+ 137 (74.3) 34 (24.5) 105 (75.5)
Stage at diagnosis of primary disease
I 28 (14.1) 0 (0.0) 28 (100.0) –
II 68 (34.4) 0 (0.0) 68 (100.0)
III 42 (21.2) 0 (0.0) 42 (100.0)
IV 60 (30.3) 49 (81.7) 11 (18.3)
Unknown 22 – 22
Breast cancer molecular subtype
Luminal A 35 (18.8) 7 (20.0) 28 (80.0) 0.315
Luminal B 118 (63.4) 31 (26.3) 87 (73.7)
Basal-like 8 (4.3) 1 (12.5) 7 (87.5)
HER+ 25 (13.4) 10 (40.0) 15 (60.0)
Unknown 34 – 34
Median Ki67% (interquartile range) 20 (10–31) 23 (15–35) 16 (10–30) 0.087
ER
Negative 21 (9.9) 2 (9.5) 19 (90.5) 0.114
Positive 183 (90.1) 47 (25.7) 136 (74.3)
Unknown or not performed 16 – 16
PgR
Negative 60 (29.4) 11 (18.3) 49 (81.7) 0.220
Positive 144 (70.6) 38 (26.4) 106 (73.6)
Unknown or not performed 16 – 16
HER2 (IHC or FISH)
Negative 162 (87.1) 38 (23.5) 124 (76.5) 0.057
Positive 24 (12.9) 10 (41.7) 14 (58.3)
Unknown or not performed 34 1 33
BM bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
Bone biopsy was performed in 58 (26.4%) cases. The median time from primary disease diagnosis to the appearance of BM in this subgroup was 79 months (95%CI: 65.0–118.1).
Time to event outcomes
Disease-free interval
Disease free-interval was calculated excluding patients with synchronous disease at bone (n = 49) and visceral (n = 2). The disease-free interval (DFI) differed slightly according to molecular subtype. The univariate hazard ratio (HR) for visceral or bone metastasis was higher in luminal B tumors (1.66, 95% confidence interval [CI] 1.1–2.5) (p = 0.023), basal-like tumors (3.92, 95% CI 1.6–9.7) (p = 0.003), and HER2-enriched tumors (1.28, 95% CI 0.7–2.4) (p = 0.442).
DFI for patients with stage I disease at diagnosis of primary BC was longer than that for stage III patients (median 67.2 months, 95% CI 53.1–96.1, vs. 58.1 months, 95% CI 41.9–73.4), with a univariate HR of 1.84 (95% CI 1.1–3.0) (p = 0.015) for the stage III group, and 0.98 (95% CI 0.6–1.5) (p = 0.931) for the stage II group. Older patients had a higher risk of metastasis (HR 1.91, 95% CI 1.4–2.7), as did those with larger tumors at diagnosis (HR: 3.7, 95% CI 1.9–7.1). Multivariate analysis confirmed these data for patients with basal-like and larger tumors (Table 5).Table 5 Median DFI and independent risk factors for metastasis.
Overall DFI bDFI
Median
(95%CI) HR from univariate Cox regression model (95%CI) HR from multivariate Cox regression model (95%CI) Median
(95%CI) HR from univariate Cox regression model (95%CI) HR from multivariate Cox regression model (95%CI)
All cases 75.7 (63.5–87.3) – – 78.2 (63.6–87.9) – –
Age at diagnosis of primary BC, years
< 55 82.1 (65.4–112.9) 1.00 1.00 89.6 (65.4–114.8) 1.00 1.00
≥ 55 65.0 (48.1–81.5) 1.91 (1.4–2.7) 1.48 (0.9–2.2) 65.0 (51.1–86.0) 1.89 (1.4–2.6) 1.27 (0.9–1.9)
BC molecular subtypes
Luminal A 101.9 (57.0–125.7) 1.00 1.00 101.9 (57.0–125.7) 1.00 1.00
Luminal B 63.5 (48.6–75.7) 1.66 (1.1–2.5) 1.46 (0.9–2.4) 63.6 (52.7–78.5) 1.54 (0.9–2.4) 1.27 (0.8–2.0)
Basal-like 30.0 (13.4–NE) 3.92 (1.6–9.7) 3.94 (1.4–11.0) 30.0 (2.1–66.1) 4.29 (1.8–10.1) 3.82 (1.4–10.6)
HER2+ 53.1 (30.9–100.1) 1.28 (0.7–2.4) 1.44 (0.7–2.9) 53.1 (47.9–100.2) 1.17 (0.6–2.2) 1.22 (0.6–2.5)
Stage at diagnosis
I 67.2 (53.1–96.1) 1.00 1.00 82.2 (53.6–125.7) 1.00 1.00
II 83.3 (66.5–99.2) 0.98 (0.6–1.5) 1.09 (0.5–2.3) 83.2 (66.5–101.9) 1.07 (0.7–1.7) 1.16 (0.6–2.4)
III 58.1 (41.9–73.4) 1.84 (1.1–3.0) 1.35 (0.5–3.2) 60.9 (41.9–75.6) 2.1 (1.3–3.5) 1.55 (0.7–3.7)
IV – – – – – –
pT at primary diagnosis of BC
T0–T2 76.7 (61.0–87.3) 1.00 1.00 78.5 (63.6–87.9) 1.00 1.00
T3–T4 20.6 (3.3–65.4) 3.7 (1.9–7.1) 3.24 (1.5–7.1) 18.6 (3.3–57.0) 4.5 (2.4–8.2) 3.02 (1.4–6.6)
pN at primary diagnosis of BC
N0 83.3 (56.1–101.9) 1.00 1.00 89.6 (61.1–118.2) 1.00 1.00
N+ 66.5 (56.3–80.0) 1.36 (0.9–1.9) 0.91 (0.5–1.7) 66.5 (57.0–79.0) 1.47 (1.0–2.1) 0.97 (0.5–1.8)
DFI disease-free interval, bDFI bone disease-free interval, HR hazard ratio, BC breast cancer, NE not evaluable from statistical software, pT primary tumour, pN pathological lymph node.
Bone disease-free interval
For this analysis, were excluded all patients with synchronous bone metastasis (n = 49). Median time to BM appearance was 78.2 months (95% confidence interval [CI] 63.6–87.9) for all patients.
Median bone disease-free interval (bDFI) was 63.5 months (95% CI 47.9–83.3) for the BM-only group at diagnosis and 86.6 months (95% CI 66.5–99.6) for those with visceral metastases. Median bDFI was 78.5 months (95% CI 63.6–87.9) in T0–T2 patients and 18.6 months (95% CI 3.3–57.0) in the T3–T4 group (p ≤ 0.001). The group with node-negative BC had a median bDFI of 8.6 months (95% CI 61.1–118.2) compared to 66.5 months (95% CI 57.0–79.0) for the node-positive subgroup (log rank test p = 0.032) (Fig. 2a,b). bDFI was significantly higher (p < 0.001) in patients aged < 55 years at diagnosis than in those ≥ 55 years, (median 89.6 [95% CI 65.4–114.8] vs. 65.0 [95% CI 51.1–86.0] months) (Supplementary Fig. 1). Multivariate analyses confirmed a higher risk for patients with basal-like and larger tumors (Table 5).Figure 2 Disease-free interval by (a) T and (b) N of primary disease.
Overall survival
Median follow-up was 46 months (range: 6–117) on 220 evaluable patients.
Seventy-four deaths were observed during follow-up. Median OS was 217.5 months (95% CI 172.5–340.1).
Molecular profile subtypes were an independent prognostic factor. Median OS (mOS) in patients with luminal A tumors was not-reached and 128.1 months (95% CI 108.0–182.6) for those with luminal B tumors, 101.2 months (95% CI 17.1–not estimable) for patients with basal-like BC, and 274.5 months (95% CI 70.3-–not estimable) for those HER2-enriched BC (p = 0.010). Patients aged ≥ 55 years and those with stage IV disease at diagnosis had a shorter mOS (128.1 months [95% CI 101.2–182.6] and 65.3 months [95% CI 41.0–80.9], respectively) than the groups diagnosed at a younger age (< 55 years) and with lower-stage disease (Supplementary Fig. 2a,b). Patients with pain at the first diagnosis of bone metastases had an mOS of 143.8 months (95% CI 98.0–247.5) with respect to 257.4 months (95% CI 135.1–not estimable) for those with no pain. mOS of the group with axial BM was 252.5 months (95% CI 182.5–343.0), 157.6 months (95% CI41.0–Not estimable) for those with appendicular BM, and 217.5 months (95% CI 100.9–Not estimable) for patients with both types of metastases (p = 0.009).
mOS of patients undergoing first-line treatment was 135.1 months (95% CI 102.9–257.4) for the chemotherapy (CH) ± biological therapy (BIO) group and 252.5 months (95%CI:202.1-not estimable) for those receiving endocrine therapy (ENDO) ± BIO, but was not-reached in patients undergoing CH + ENDO (p = 0.0305). Patients aged ≥ 55 years (HR 2.92, 95% CI 1.4–6.0), those with luminal B (HR 4.10, 95% CI 1.5–11.1), stage IV disease (HR 8.69, 95% CI 2.6–28.9) or axial + appendicular or other site of BM (HR:2.20, 95% CI 1.1–4.6) had a higher risk of death, while those with no pain at BM diagnosis (HR 0.49, 95% CI 0.2–0.9) and patients receiving ENDO ± BIO (HR:0.40, 95% CI 0.2–0.8) had a better prognosis considering multivariate Cox regression model (Supplementary Table 2).
OS from diagnosis of metastatic disease
The median OS for patients with metastatic disease (metOS) was 66.8 months (95% CI 52.1–79.2). The molecular profile of subtypes was an independent prognostic factors according to metOS. A multivariate Cox regression model confirmed a poorer prognosis for patients with luminal B subtype (HR 3.67, 95% CI 1.5–8.7) (Supplementary Table 2).
Progression-free survival
Disease progression occurred in 167 patients. Median progression-free survival (PFS) was 15.1 months (95% CI 12.6–18.4). With respect to first-line treatment, median PFS was 13.4 months (95% CI 10.0–16.6) in the CH ±BIO arm, 17.3 months (95% CI 12.0–23.6) in the ENDO ± BIO group and 32.0 months (95% CI 12.7-Not estimable) in CH + ENDO patients. None of analyzed prognostic factors were found as statistically significant in univariate analysis, even if a HR of 0.51 (95% CI 0.27–0.95) was observed for patients treated with CH + ENDO with respect to those given CH alone after the first diagnosis of metastasis (p = 0.0849) (Supplementary Fig. 3) in univariate analysis. No differences in terms of time to disease progression were seen between synchronous and metachronous BM, BOM vs. BVM, first-line treatment, number and type of BM, and presence of pain at diagnosis. The presence of SREs at diagnosis did not have an impact on disease progression (Supplementary Table 3).
Bone metastasis progression-free survival
Median BM PFS was 45.9 months (95% CI 30.8–63.0). Older patients had a higher risk for progression to bone (HR: 1.51, 95% CI 1.1–2.1) in univariate analysis (Supplementary Table 3).
Time to first SRE
Ninety-eight (44.5%) patients had at least one SRE during the course of their metastatic disease. Patients treated with zoledronic acid or pamidronate had a similar HR for SREs with respect to untreated patients (HR 1.32, 95% CI 0.74–2.38), while those taking denosumab had a HR of 0.20 (95% CI 0.04–0.87), indicating a reduced risk of SRE (Supplementary Fig. 4). Supplementary data are reported in Appendix 2.
Discussion
Bone metastases represent a common complication of cancer, their incidence reaching around 65% in BC2. There are still aspects of bone metastatic disease that need to be further investigated15,16.
As reported in previous studies, our case series showed a majority of lytic bone metastases17,18. The nature (lytic or not) of BM would not appear to impact patient outcome. Small BC tumors (T0–T2) were associated with metachronous BM, with a time to bone involvement of 65.1 months after the primary diagnosis of BC, indicating that the information collected also regarded patients with latent BM. This subgroup possesses the clinical phenotype of bone metastatic cells characterized by dormancy in which adjuvant BTT could prove useful to prevent BM formation19. The mOS from the diagnosis of distant disease (5.5 years) was similar to that reported in other studies, whereas mOS from the primary BC diagnosis differed20–22. Such findings reflect the good prognosis of the primary BC patients included in our study, representing a real-world population.
Recent studies on a population-based cancer registry and a National Cancer Database observed that patients aged < 60 years now show better survival than those reported in previous studies in which younger age and premenopausal status were associated with poorer survival22–24. Our study had similar findings, with improved mOS from the time of diagnosis of metastastic disease and primary BC in patients < 55 years and < 65 years, respectively.
Our data are also consistent with previous literature reporting that luminal BC subtype confers an independent survival benefit regardless of tumor receptor status25,26.
The initial stage of disease at BC diagnosis represented an important prognostic factor for survival and is consistent with the literature on this topic27,28. Some preclinical and clinical studies have reported promising results for concurrent ENDO + CH in postmenopausal patients with metastatic hormone-positive BC29,30. In line with these findings, our patients undergoing the ENDO + CH combination showed a slight benefit in terms of mPFS with respect to those treated with ENDO + CH ± BIO. These fascinating suggestions warrant further exploration and validation prospective clinical trials.
Previous studies have shown a better prognosis for BOM patients than for those with BVM. However, in our study BOM and BVM groups had a similar mOS which may be attributable to a conditioning effect of the molecular BC subtype and also to new treatments available.
A recently published study on BOM reported no correlation between bone pain and survival. Our results are in line with these findings in both BOM and BVM groups. BM localization proved to have a prognostic value in our case series, an appendicular site negatively impacting mOS more than axial or mixed localizations. In a retrospective study conducted by Parkes et al., BOM patients with axial localisation had a mOS from the diagnosis of distant disease of 5.62 years compared to 6.78 years for those with appendicular BM and 4.58 years the appendicular + axial BM group31. A possible explanation for this could be the higher incidence of axial bone metastases in luminal BC.
Another interesting finding of our study was that patients with single or oligo- metastases had a better prognosis than those with multiple bone lesions. Although there is already evidence of this for the former32, interest in oligo-metastatic disease has recently come to the fore because of its challenging management33,34.
It has been seen that changes in BC cell biology occur between primary tumors and metastases35,36. In our study a significant difference in PgR expression was observed between primary BC and metastatic bone lesions. Clinicians should take this into account in cases of disease recurrence more than 5 years after the primary diagnosis.
Age was found to have a significant impact on OS. This is in line with retrospective works published on BC and BM patients in which age was found to be an independent prognostic factor30.
Finally, our data confirm the protective effect of denosumab in preventing SREs, which leveled off over time. Albeit with an incidence reducing over time.
One of the limitations of our study is the patient sample even though it’s consistent with other studies in which patients were followed prospectively in a dedicated database on BM and not extrapolated from large registries28,32. Another limit is the lack of information available on specific treatments, a result of opting not to enter a large amount of data into the database. To overcome this we grouped treatments into specific categories.
In contrast, the strengths of our study are its collection of prospective data on BM and their clinical evolution and the fact that it constitutes a national representative study population for this disease setting.
In conclusion, the Italian BMDB represents an invaluable tool to better understand the natural history of bone metastases from breast cancer and improve their management. The Italian BMDB continues to enroll patients also in other solid tumors to increase the case series and give more answer to clinician questions.
Supplementary Information
Supplementary Information.
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Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-021-83749-1.
Acknowledgements
The authors thanks all the other members of Banca Dati Metastasi Ossee Study Team: Luigi Cavanna (A.O. Piacenza, Piacenza, Italy), Antonio Maestri (S. Maria della Scaletta Hospital, Imola, Bologna), Francesco Ferraù (Medical Oncology Division, San Vincenzo Hospital, Taormina, Italy), Maria Banzi (Medical Oncology Unit, Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy), Bruno Daniele (Gaetano Rummo Hospital, Benevento, Italy), Sergio Fava (Ospedale Civile di Legnano, Legnano, Italy), Gaetano Lanzetta (Medical Oncology Unit, Istituto Neurotramutologico Italiano, Grottaferrata, Italy). The authors thanks Gráinne Tierney and Cristiano Verna for editorial assistance.
Author contributions
Conception and design: A.B., T.I. and F.F. IT support: R.V. Provision of study materials or patients: A.B., T.I., F.F., M.F., M.R.F., F.A., R.B., E.C., G.P., F.S., N.R., L.G., S.D.B., G.D.M., V.F. and F.R. Data analysis and interpretation: A.B., T.I., F.F., M.R.F., F.A., M.F., R.B., G.P., F.S. and E.C. Manuscript writing and final approval of manuscript: All authors.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The datasets gathered and analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | DENOSUMAB | DrugsGivenReaction | CC BY | 33619285 | 18,321,151 | 2021-02-22 |
What was the outcome of reaction 'Death'? | First prospective data on breast cancer patients from the multicentre italian bone metastasis database.
Bone metastases (BM) are still the main cause of morbidity in cancer patients because of skeletal-related events (SREs) that reduce quality of life. They have also led to increased social and healthcare costs. At present, data available on BM are insufficient. This was a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 months' follow-up. Information on patients at the first diagnosis of BM, including demographics and characteristics of the primary tumor and BM. Data were periodically updated by participating centres and reviewed by the coordinator centre. From October 2014 to July 2019, 618 patients with BM from solid tumors were enrolled and 220 were eligible for the present study. Median age was 62 years (range 26-86). Median follow-up was 34 months (range 6-149). At the time of enrolment, 109 (50%) had only BM (BOM) and 109 (50%) had concomitant visceral lesions and BM (BVM). Median time-to-first BM was 47 months (range 0-312) in BOM and 78.6 months in BVM patients. Disease-free interval differed on the basis of BC molecular subtype and stage. Ninety-eight BM patients had at least on SRE. Zoledronate was used in 69.1% of cases and denosumab in 28.3%. First-line treatment was hormone-based (50.7%), chemotherapy-based (38.7%) or chemotherapy- + hormone therapy-based (9.7%). Median progression-free and overall survival were 15.1 months (95% CI 12.6-18.4) and 66.8 months (95% CI 52.1-79.2), respectively. Our prospective study could substantially help to better understand the natural history of BM from BC.
Introduction
Breast cancer (BC) is the most common malignancy and a major cause of morbidity and mortality among women. The mortality rate has decreased thanks to improved diagnostic procedures, screening and more advanced treatments. However, the rate of recurrence in distant organs is still fairly high, ranging from 20 to 30%1,2.
Bone is the most common site of metastasis in BC and significantly impacts patient survival3–5.
Bone metastases (BMs) represent an important clinical-epidemiological issue in oncology because their diagnosis and treatment are often necessarily handled by several specialists, resulting in fragmented patient information6. For these reasons, great efforts have been made to develop a new scientific and clinical branch of medicine, i.e. Osteoncology7.
The major problem faced by BM patients is the risk of skeletal complications defined as skeletal-related events (SREs) all of which are highly detrimental to quality of life and survival2,8,9.
There is still limited information available on BM clinical presentation, the difference in disease response between bone and visceral sites, and the difference in prognosis between solitary, oligometastatic and multiple sites or axial and trunk bone metastases10. A clearer understanding of their natural evolution would thus help us to identify new strategies capable of reducing both BM incidence and morbidity.
The risk of SREs in BC patients with BM has been the focus of numerous studies11–13. However, their findings are of limited value because of their poor generalizability with respect to current clinical practice. In the retrospective studies, authors usually considered a lengthy time period during which available therapies and clinical practice may have changed substantially. In the prospective studies, patients were followed for a short period (24 months) and data were extrapolated from a BC database rather than from a database dedicated to BM. Furthermore, in recent years, new therapeutic options have become available. There has also been growing interest in BM since dedicated multidisciplinary groups began to emerge14.
The main aims of this prospective multicenter study were to evaluate the evolution of skeletal disease in BC patients, assess the impact of BM on disease outcome, examine the role of a number of clinical-pathological parameters in predicting survival, and further our understanding of the natural history of patients with BM from BC.
Materials and methods
This was a multicentre prospective observational study of patients with BM from BC with at least 6 months follow-up, enrolled into the prospective Italian Bone Metastases Data Base (BMDB). The study was approved by the Local Ethics Committee of each participating centre and carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. List of participating centers was provided in Supplementary Table 1. Written informed consent was obtained from all patients. Information on data source is provided in Appendix 1.
Data extraction and measure definition
The evolution of skeletal disease in BC patients was evaluated by extracting data from the BMDB for patients who had a first diagnosis of BC with a synchronous (within 2 months) or metachronous diagnosis of bone metastasis and were followed up for at least 6 months after the BM diagnosis.
Time to event outcomes were defined as follows: disease-free interval (DFI) was the time from primary BC disease to the appearance of the first metastasis (bone or visceral), and bone disease-free interval (bDFI) was the time between diagnosis of primary BC and first diagnosis of BM. Overall survival (OS) was calculated as the time from the date of the diagnosis of primary BC to the date of death. OS from metastatic disease (metOS) was calculated as the time from the diagnosis of metastasis (either bone or visceral) to death. Progression-free survival (PFS) was the time between the date of the first diagnosis of bone metastasis and date of the first documented evidence of disease progression (bone or visceral) and death. Bone PFS (bPFS) was the time between the date of the first diagnosis of BM and first progression to bone and death. Time-to-first SRE was the time between the first diagnosis of BM and the first SRE event. Patients without events of interest were censored at the date of the last follow-up visit.
Statistical analysis
Descriptive statistics are used to summarize baseline patient characteristics, BM characteristics and treatment patterns. Continuous variables are presented using median and range or interquartile range. The Wilcoxon rank-sum test was used for continuous variables, together with the chi-squared test or Fisher’s exact test, as appropriate. McNemar’s test was used in cases of paired data. Time-to-event measures were analysed using the Kaplan–Meier method, and the nonparametric log-rank test was used to evaluate the role of stratification factor. We used the Cox proportional hazards regression model to estimate hazard ratios (HRs) and relative 95% confidence intervals (CI) of potential clinical prognostic factors for time-to-event outcomes.
All statistical analyses were performed using STATA/MP 15.0 for Windows (StataCorp LLP, College Station, TX, USA).
Results
Patient characteristics
From October 1st 2014 to June 30th 2018, 618 patients with BM from any solid tumor were registered in the Italian BMDB. Three hundred and nine had BC as the primary site of disease and 220/309 with at least 6 months’ follow up were included in the present analysis (Fig. 1). Median age was 62 (range 26–85) years.Figure 1 Study flow diagram.
At the time of the first diagnosis of BM, 152 (92.1%) patients showed a good ECOG PS (0–1). Forty-nine (22.3%) patients were diagnosed with BM synchronous to the primary tumor, while metachronous BM were found in 171 patients.
Bone-only metastases (BOM) were found in 109 (50.0%) patients, while the remaining 109 had concomitant visceral and BM (BVM). Histological and biological characteristics of the primary BC are shown in Tables 1 and 2. Luminal A and B tumors were more frequently associated with BOM, whereas basal-like or HER2-enriched BC subtypes more often showed BVM (p = 0.012). A higher, albeit not significant, Ki-67 value was observed for patients with BVM (p = 0.074). The majority of patients had T0-T2 (n = 159, 85%) and node-positive tumors (n = 138, 74.6%) at diagnosis (Table 3), the former associated with a higher rate of metachronous BM than synchronous BM (83.2% and 16.8%, respectively) (p < 0.001) (Table 4). Patients with N0 primary tumors had a higher incidence of metachronous BM than synchronous (95.8% and 4.2%, respectively) (p = 0.001). No difference between BOM or BVM according to node status (node negative vs. node positive tumors) was observed. Both node-negative and node-positive patients showed a high rate of metachronous BM (95.8% and 75.5%, respectively), even if in node-negative patients there is a significantly higher proportion of patients with metachronous BM.Table 1 Patient characteristics at baseline and at onset of BM.
Patients (n = 220)
Median age, years (range) 62 (26–85)
No. (%)
Age at diagnosis of primary BM, years
< 65 133 (60.5)
65 87 (69.5)
ECOG PS at diagnosis of primary BM
0–1 152 (92.1)
≥ 2 13 (7.9)
Unknown 55
Histology
Ductal carcinoma 166 (75.5)
Lobular carcinoma 29 (13.0)
Mixed ductal and lobular carcinoma 11 (5.0)
Adenocarcinoma, NOS 9 (4.0)
Signet ring cell carcinoma 1 (0.5)
Other 4 (2.0)
pT at primary diagnosis of BC
T0–T2 159 (85.0)
T3–T4 28 (15.0)
Tx 31
pN at primary diagnosis of BC
N0 47 (25.4)
N+ 138 (74.6)
Nx 33
Stage at diagnosis of primary disease
I 28 (14.1)
II 68 (34.3)
III 42 (21.2)
IV 60 (30.3)
Unknown 22
BC molecular subtype
Luminal A 35 (18.8)
Luminal B 118 (63.4)
Basal-like 8 (4.3)
HER+ 25 (13.4)
Unknown 34
Grading
G1 6 (3.7)
G2 85 (52.5)
G3 71 (43.8)
Unknown 58
Bone metastasis
Synchronous 49 (22.3)
Metachronous 171 (77.7)
BOM 109 (50.0)
BVM 109 (50.0)
BM bone metastasis, ECOG PS Eastern Cooperative Oncology Group Performance Status, NOS not otherwise specified, BC breast cancer, pT primary tumour, pN pathological lymph node, Nx unknown lymph node stage, G grade, BOM bone-only metastasis, BVM visceral and bone metastasis.
Table 2 Biomarker characteristics at diagnosis of primary BC and at onset of BM.
BC characteristics At diagnosis At the onset of bone metastasis
Positive* (%) Negative* (%) NA Positive* (%) Negative* (%) NA
ER 183 (89.7) 21 (10.3) 16 48 (88.9) 6 (11.1) 166
PgR 144 (70.6) 60 (29.4) 16 24 (45.3) 29 (54.7) 167
< 15% ≥ 15% NA < 15% ≥ 15% NA
Ki-67 145 (79.7) 37 (20.3) 38 29 (65.9) 15 (34.1) 176
Positive/(+ + +) Negative/0–2 + NA Positive/(+ + +) Negative/0–2 + NA
HER2 (IHC or FISH) 24 (12.9) 162 (87.1) 34 7 (13.7) 44 (86.3) 169
BC breast cancer, BM bone metastasis, ER oestrogen receptor, PgR progesterone receptor, NA not available, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
*For ER and PgR, positive if ≥ 10%, negative if < 10%.
Table 3 Baseline patient characteristics in relation to presence of visceral metastases.
Baseline BC characteristics No. patients
(n = 218) BOM (n = 109)
No. (%) BVM (n = 109)
No. (%) p-value
Age at diagnosis of bone metastasis, years
< 65 108 (49.1) 70 (53.0) 62 (47.0) 0.268
≥ 65 112 (50.9) 39 (45.3) 47 (54.7)
pT at primary diagnosis of breast cancer
T0–T2 159 (85.0) 84 (52.8) 75 (47.2) 0.531
T3–T4 28 (15.0) 13 (46.4) 15 (53.6)
pN at primary diagnosis of breast cancer
N0 47 (25.4) 26 (55.3) 21 (44.7) 0.330
N+ 138 (74.6) 65 (47.1) 73 (52.9)
Stage at diagnosis of primary disease
I 27 (13.8) 16 (59.3) 11 (40.7) 0.621
II 67 (34.2) 31 (46.3) 36 (53.7)
III 42 (21.4) 23 (54.8) 19 (45.2)
IV 60 (30.6) 33 (55.0) 27 (45.0)
Unknown 22 6 16
Breast cancer molecular subtype
Luminal A 35 (19.0) 26 (74.3) 9 (25.7) 0.012
Luminal B 118 (64.1) 60 (50.8) 58 (49.2)
Basal-like 7 (3.8) 2 (28.6) 5 (71.4)
HER+ 24 (13.1) 9 (37.5) 15 (62.5)
Unknown 34 12 22
Median Ki67% (interquartile range) 20 (10–31) 16 (8–30) 20 (10–35) 0.074
ER
Negative 19 (9.4) 6 (31.6) 13 (68.4) 0.075
Positive 183 (90.6) 97 (53.1) 86 (46.9)
Unknown or not performed 16 6 10
PgR
Negative 58 (28.7) 29 (50.0) 29 (50.0) 0.858
Positive 144 (71.3) 74 (51.4) 70 (48.6)
Unknown or not performed 16 6 10
HER2 (IHC or FISH)
Negative 161 (87.5) 89 (55.3) 72 (44.7) 0.066
Positive 23 (12.5) 8 (34.8) 15 (65.2)
Unknown or not performed 34 12 22
Adjuvant therapy
No 73 (33.4) 35 (47.9) 38 (52.1) 0.632
Yes 144 (66.1) 74 (51.4) 70 (48.6)
Neoadjuvant therapy
No 196 (91.2) 97 (49.5) 99 (50.5) 0.484
Yes 19 (8.8) 11 (57.9) 8 (42.1)
BC breast cancer, BOM bone-only metastasis, BVM visceral and bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
Table 4 Baseline patient characteristics in relation to synchronous or metachronous metastases.
Baseline BC characteristics No. patients
(n = 220) Synchronous BM
(n = 49)
No. (%) Metachronous BM
(n = 171)
No. (%) p-value
Age at diagnosis of bone metastasis, years
< 65 133 (49.1) 32 (24.1) 101 (75.9) 0.431
≥ 65 87 (50.9) 17 (19.5) 70 (80.5)
pT at primary diagnosis of breast cancer
T0–T2 161 (85.0) 27 (16.8) 134 (83.2) < 0.001
T3–T4 28 (15.0) 15 (53.6) 13 (46.4)
pN at primary diagnosis of breast cancer
N0 48 (25.6) 2 (4.2) 46 (95.8) 0.001
N+ 137 (74.3) 34 (24.5) 105 (75.5)
Stage at diagnosis of primary disease
I 28 (14.1) 0 (0.0) 28 (100.0) –
II 68 (34.4) 0 (0.0) 68 (100.0)
III 42 (21.2) 0 (0.0) 42 (100.0)
IV 60 (30.3) 49 (81.7) 11 (18.3)
Unknown 22 – 22
Breast cancer molecular subtype
Luminal A 35 (18.8) 7 (20.0) 28 (80.0) 0.315
Luminal B 118 (63.4) 31 (26.3) 87 (73.7)
Basal-like 8 (4.3) 1 (12.5) 7 (87.5)
HER+ 25 (13.4) 10 (40.0) 15 (60.0)
Unknown 34 – 34
Median Ki67% (interquartile range) 20 (10–31) 23 (15–35) 16 (10–30) 0.087
ER
Negative 21 (9.9) 2 (9.5) 19 (90.5) 0.114
Positive 183 (90.1) 47 (25.7) 136 (74.3)
Unknown or not performed 16 – 16
PgR
Negative 60 (29.4) 11 (18.3) 49 (81.7) 0.220
Positive 144 (70.6) 38 (26.4) 106 (73.6)
Unknown or not performed 16 – 16
HER2 (IHC or FISH)
Negative 162 (87.1) 38 (23.5) 124 (76.5) 0.057
Positive 24 (12.9) 10 (41.7) 14 (58.3)
Unknown or not performed 34 1 33
BM bone metastasis, pT primary tumour, pN pathological lymph node, ER oestrogen receptor, PgR progesterone receptor, IHC immunohistochemistry, FISH fluorescence in situ hybridisation.
Bone biopsy was performed in 58 (26.4%) cases. The median time from primary disease diagnosis to the appearance of BM in this subgroup was 79 months (95%CI: 65.0–118.1).
Time to event outcomes
Disease-free interval
Disease free-interval was calculated excluding patients with synchronous disease at bone (n = 49) and visceral (n = 2). The disease-free interval (DFI) differed slightly according to molecular subtype. The univariate hazard ratio (HR) for visceral or bone metastasis was higher in luminal B tumors (1.66, 95% confidence interval [CI] 1.1–2.5) (p = 0.023), basal-like tumors (3.92, 95% CI 1.6–9.7) (p = 0.003), and HER2-enriched tumors (1.28, 95% CI 0.7–2.4) (p = 0.442).
DFI for patients with stage I disease at diagnosis of primary BC was longer than that for stage III patients (median 67.2 months, 95% CI 53.1–96.1, vs. 58.1 months, 95% CI 41.9–73.4), with a univariate HR of 1.84 (95% CI 1.1–3.0) (p = 0.015) for the stage III group, and 0.98 (95% CI 0.6–1.5) (p = 0.931) for the stage II group. Older patients had a higher risk of metastasis (HR 1.91, 95% CI 1.4–2.7), as did those with larger tumors at diagnosis (HR: 3.7, 95% CI 1.9–7.1). Multivariate analysis confirmed these data for patients with basal-like and larger tumors (Table 5).Table 5 Median DFI and independent risk factors for metastasis.
Overall DFI bDFI
Median
(95%CI) HR from univariate Cox regression model (95%CI) HR from multivariate Cox regression model (95%CI) Median
(95%CI) HR from univariate Cox regression model (95%CI) HR from multivariate Cox regression model (95%CI)
All cases 75.7 (63.5–87.3) – – 78.2 (63.6–87.9) – –
Age at diagnosis of primary BC, years
< 55 82.1 (65.4–112.9) 1.00 1.00 89.6 (65.4–114.8) 1.00 1.00
≥ 55 65.0 (48.1–81.5) 1.91 (1.4–2.7) 1.48 (0.9–2.2) 65.0 (51.1–86.0) 1.89 (1.4–2.6) 1.27 (0.9–1.9)
BC molecular subtypes
Luminal A 101.9 (57.0–125.7) 1.00 1.00 101.9 (57.0–125.7) 1.00 1.00
Luminal B 63.5 (48.6–75.7) 1.66 (1.1–2.5) 1.46 (0.9–2.4) 63.6 (52.7–78.5) 1.54 (0.9–2.4) 1.27 (0.8–2.0)
Basal-like 30.0 (13.4–NE) 3.92 (1.6–9.7) 3.94 (1.4–11.0) 30.0 (2.1–66.1) 4.29 (1.8–10.1) 3.82 (1.4–10.6)
HER2+ 53.1 (30.9–100.1) 1.28 (0.7–2.4) 1.44 (0.7–2.9) 53.1 (47.9–100.2) 1.17 (0.6–2.2) 1.22 (0.6–2.5)
Stage at diagnosis
I 67.2 (53.1–96.1) 1.00 1.00 82.2 (53.6–125.7) 1.00 1.00
II 83.3 (66.5–99.2) 0.98 (0.6–1.5) 1.09 (0.5–2.3) 83.2 (66.5–101.9) 1.07 (0.7–1.7) 1.16 (0.6–2.4)
III 58.1 (41.9–73.4) 1.84 (1.1–3.0) 1.35 (0.5–3.2) 60.9 (41.9–75.6) 2.1 (1.3–3.5) 1.55 (0.7–3.7)
IV – – – – – –
pT at primary diagnosis of BC
T0–T2 76.7 (61.0–87.3) 1.00 1.00 78.5 (63.6–87.9) 1.00 1.00
T3–T4 20.6 (3.3–65.4) 3.7 (1.9–7.1) 3.24 (1.5–7.1) 18.6 (3.3–57.0) 4.5 (2.4–8.2) 3.02 (1.4–6.6)
pN at primary diagnosis of BC
N0 83.3 (56.1–101.9) 1.00 1.00 89.6 (61.1–118.2) 1.00 1.00
N+ 66.5 (56.3–80.0) 1.36 (0.9–1.9) 0.91 (0.5–1.7) 66.5 (57.0–79.0) 1.47 (1.0–2.1) 0.97 (0.5–1.8)
DFI disease-free interval, bDFI bone disease-free interval, HR hazard ratio, BC breast cancer, NE not evaluable from statistical software, pT primary tumour, pN pathological lymph node.
Bone disease-free interval
For this analysis, were excluded all patients with synchronous bone metastasis (n = 49). Median time to BM appearance was 78.2 months (95% confidence interval [CI] 63.6–87.9) for all patients.
Median bone disease-free interval (bDFI) was 63.5 months (95% CI 47.9–83.3) for the BM-only group at diagnosis and 86.6 months (95% CI 66.5–99.6) for those with visceral metastases. Median bDFI was 78.5 months (95% CI 63.6–87.9) in T0–T2 patients and 18.6 months (95% CI 3.3–57.0) in the T3–T4 group (p ≤ 0.001). The group with node-negative BC had a median bDFI of 8.6 months (95% CI 61.1–118.2) compared to 66.5 months (95% CI 57.0–79.0) for the node-positive subgroup (log rank test p = 0.032) (Fig. 2a,b). bDFI was significantly higher (p < 0.001) in patients aged < 55 years at diagnosis than in those ≥ 55 years, (median 89.6 [95% CI 65.4–114.8] vs. 65.0 [95% CI 51.1–86.0] months) (Supplementary Fig. 1). Multivariate analyses confirmed a higher risk for patients with basal-like and larger tumors (Table 5).Figure 2 Disease-free interval by (a) T and (b) N of primary disease.
Overall survival
Median follow-up was 46 months (range: 6–117) on 220 evaluable patients.
Seventy-four deaths were observed during follow-up. Median OS was 217.5 months (95% CI 172.5–340.1).
Molecular profile subtypes were an independent prognostic factor. Median OS (mOS) in patients with luminal A tumors was not-reached and 128.1 months (95% CI 108.0–182.6) for those with luminal B tumors, 101.2 months (95% CI 17.1–not estimable) for patients with basal-like BC, and 274.5 months (95% CI 70.3-–not estimable) for those HER2-enriched BC (p = 0.010). Patients aged ≥ 55 years and those with stage IV disease at diagnosis had a shorter mOS (128.1 months [95% CI 101.2–182.6] and 65.3 months [95% CI 41.0–80.9], respectively) than the groups diagnosed at a younger age (< 55 years) and with lower-stage disease (Supplementary Fig. 2a,b). Patients with pain at the first diagnosis of bone metastases had an mOS of 143.8 months (95% CI 98.0–247.5) with respect to 257.4 months (95% CI 135.1–not estimable) for those with no pain. mOS of the group with axial BM was 252.5 months (95% CI 182.5–343.0), 157.6 months (95% CI41.0–Not estimable) for those with appendicular BM, and 217.5 months (95% CI 100.9–Not estimable) for patients with both types of metastases (p = 0.009).
mOS of patients undergoing first-line treatment was 135.1 months (95% CI 102.9–257.4) for the chemotherapy (CH) ± biological therapy (BIO) group and 252.5 months (95%CI:202.1-not estimable) for those receiving endocrine therapy (ENDO) ± BIO, but was not-reached in patients undergoing CH + ENDO (p = 0.0305). Patients aged ≥ 55 years (HR 2.92, 95% CI 1.4–6.0), those with luminal B (HR 4.10, 95% CI 1.5–11.1), stage IV disease (HR 8.69, 95% CI 2.6–28.9) or axial + appendicular or other site of BM (HR:2.20, 95% CI 1.1–4.6) had a higher risk of death, while those with no pain at BM diagnosis (HR 0.49, 95% CI 0.2–0.9) and patients receiving ENDO ± BIO (HR:0.40, 95% CI 0.2–0.8) had a better prognosis considering multivariate Cox regression model (Supplementary Table 2).
OS from diagnosis of metastatic disease
The median OS for patients with metastatic disease (metOS) was 66.8 months (95% CI 52.1–79.2). The molecular profile of subtypes was an independent prognostic factors according to metOS. A multivariate Cox regression model confirmed a poorer prognosis for patients with luminal B subtype (HR 3.67, 95% CI 1.5–8.7) (Supplementary Table 2).
Progression-free survival
Disease progression occurred in 167 patients. Median progression-free survival (PFS) was 15.1 months (95% CI 12.6–18.4). With respect to first-line treatment, median PFS was 13.4 months (95% CI 10.0–16.6) in the CH ±BIO arm, 17.3 months (95% CI 12.0–23.6) in the ENDO ± BIO group and 32.0 months (95% CI 12.7-Not estimable) in CH + ENDO patients. None of analyzed prognostic factors were found as statistically significant in univariate analysis, even if a HR of 0.51 (95% CI 0.27–0.95) was observed for patients treated with CH + ENDO with respect to those given CH alone after the first diagnosis of metastasis (p = 0.0849) (Supplementary Fig. 3) in univariate analysis. No differences in terms of time to disease progression were seen between synchronous and metachronous BM, BOM vs. BVM, first-line treatment, number and type of BM, and presence of pain at diagnosis. The presence of SREs at diagnosis did not have an impact on disease progression (Supplementary Table 3).
Bone metastasis progression-free survival
Median BM PFS was 45.9 months (95% CI 30.8–63.0). Older patients had a higher risk for progression to bone (HR: 1.51, 95% CI 1.1–2.1) in univariate analysis (Supplementary Table 3).
Time to first SRE
Ninety-eight (44.5%) patients had at least one SRE during the course of their metastatic disease. Patients treated with zoledronic acid or pamidronate had a similar HR for SREs with respect to untreated patients (HR 1.32, 95% CI 0.74–2.38), while those taking denosumab had a HR of 0.20 (95% CI 0.04–0.87), indicating a reduced risk of SRE (Supplementary Fig. 4). Supplementary data are reported in Appendix 2.
Discussion
Bone metastases represent a common complication of cancer, their incidence reaching around 65% in BC2. There are still aspects of bone metastatic disease that need to be further investigated15,16.
As reported in previous studies, our case series showed a majority of lytic bone metastases17,18. The nature (lytic or not) of BM would not appear to impact patient outcome. Small BC tumors (T0–T2) were associated with metachronous BM, with a time to bone involvement of 65.1 months after the primary diagnosis of BC, indicating that the information collected also regarded patients with latent BM. This subgroup possesses the clinical phenotype of bone metastatic cells characterized by dormancy in which adjuvant BTT could prove useful to prevent BM formation19. The mOS from the diagnosis of distant disease (5.5 years) was similar to that reported in other studies, whereas mOS from the primary BC diagnosis differed20–22. Such findings reflect the good prognosis of the primary BC patients included in our study, representing a real-world population.
Recent studies on a population-based cancer registry and a National Cancer Database observed that patients aged < 60 years now show better survival than those reported in previous studies in which younger age and premenopausal status were associated with poorer survival22–24. Our study had similar findings, with improved mOS from the time of diagnosis of metastastic disease and primary BC in patients < 55 years and < 65 years, respectively.
Our data are also consistent with previous literature reporting that luminal BC subtype confers an independent survival benefit regardless of tumor receptor status25,26.
The initial stage of disease at BC diagnosis represented an important prognostic factor for survival and is consistent with the literature on this topic27,28. Some preclinical and clinical studies have reported promising results for concurrent ENDO + CH in postmenopausal patients with metastatic hormone-positive BC29,30. In line with these findings, our patients undergoing the ENDO + CH combination showed a slight benefit in terms of mPFS with respect to those treated with ENDO + CH ± BIO. These fascinating suggestions warrant further exploration and validation prospective clinical trials.
Previous studies have shown a better prognosis for BOM patients than for those with BVM. However, in our study BOM and BVM groups had a similar mOS which may be attributable to a conditioning effect of the molecular BC subtype and also to new treatments available.
A recently published study on BOM reported no correlation between bone pain and survival. Our results are in line with these findings in both BOM and BVM groups. BM localization proved to have a prognostic value in our case series, an appendicular site negatively impacting mOS more than axial or mixed localizations. In a retrospective study conducted by Parkes et al., BOM patients with axial localisation had a mOS from the diagnosis of distant disease of 5.62 years compared to 6.78 years for those with appendicular BM and 4.58 years the appendicular + axial BM group31. A possible explanation for this could be the higher incidence of axial bone metastases in luminal BC.
Another interesting finding of our study was that patients with single or oligo- metastases had a better prognosis than those with multiple bone lesions. Although there is already evidence of this for the former32, interest in oligo-metastatic disease has recently come to the fore because of its challenging management33,34.
It has been seen that changes in BC cell biology occur between primary tumors and metastases35,36. In our study a significant difference in PgR expression was observed between primary BC and metastatic bone lesions. Clinicians should take this into account in cases of disease recurrence more than 5 years after the primary diagnosis.
Age was found to have a significant impact on OS. This is in line with retrospective works published on BC and BM patients in which age was found to be an independent prognostic factor30.
Finally, our data confirm the protective effect of denosumab in preventing SREs, which leveled off over time. Albeit with an incidence reducing over time.
One of the limitations of our study is the patient sample even though it’s consistent with other studies in which patients were followed prospectively in a dedicated database on BM and not extrapolated from large registries28,32. Another limit is the lack of information available on specific treatments, a result of opting not to enter a large amount of data into the database. To overcome this we grouped treatments into specific categories.
In contrast, the strengths of our study are its collection of prospective data on BM and their clinical evolution and the fact that it constitutes a national representative study population for this disease setting.
In conclusion, the Italian BMDB represents an invaluable tool to better understand the natural history of bone metastases from breast cancer and improve their management. The Italian BMDB continues to enroll patients also in other solid tumors to increase the case series and give more answer to clinician questions.
Supplementary Information
Supplementary Information.
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Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-021-83749-1.
Acknowledgements
The authors thanks all the other members of Banca Dati Metastasi Ossee Study Team: Luigi Cavanna (A.O. Piacenza, Piacenza, Italy), Antonio Maestri (S. Maria della Scaletta Hospital, Imola, Bologna), Francesco Ferraù (Medical Oncology Division, San Vincenzo Hospital, Taormina, Italy), Maria Banzi (Medical Oncology Unit, Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy), Bruno Daniele (Gaetano Rummo Hospital, Benevento, Italy), Sergio Fava (Ospedale Civile di Legnano, Legnano, Italy), Gaetano Lanzetta (Medical Oncology Unit, Istituto Neurotramutologico Italiano, Grottaferrata, Italy). The authors thanks Gráinne Tierney and Cristiano Verna for editorial assistance.
Author contributions
Conception and design: A.B., T.I. and F.F. IT support: R.V. Provision of study materials or patients: A.B., T.I., F.F., M.F., M.R.F., F.A., R.B., E.C., G.P., F.S., N.R., L.G., S.D.B., G.D.M., V.F. and F.R. Data analysis and interpretation: A.B., T.I., F.F., M.R.F., F.A., M.F., R.B., G.P., F.S. and E.C. Manuscript writing and final approval of manuscript: All authors.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
The datasets gathered and analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests. | Fatal | ReactionOutcome | CC BY | 33619285 | 18,321,151 | 2021-02-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal wall haematoma'. | Splenic infarction and spontaneous rectus sheath hematomas in COVID-19 patient.
Multiple studies and reports have suggested that coronavirus disease-19 (COVID-19) promotes arterial and venous thrombotic events in multiple organ systems, although the mechanism leading to a hypercoagulable state is still unknown. Few cases of splenic infarction associated with COVID-19 have been reported, of which half were found incidentally upon autopsy. This may be due to a clinically silent presentation or the symptoms being wrongfully attributed to pain caused by the effects of COVID-19. Due to the rarity of the condition and its lack of consistent symptomatology, splenic thromboembolism can be difficult to diagnose. Awareness of the condition and high clinical suspicion will help the clinician identify and manage the problem. Hemorrhage in patients with COVID-19 is uncommon in the hypercoagulable state that threatens thrombus formation in patients with COVID-19 infection. Despite prophylactic treatment with anticoagulation therapies, patients are more prone to developing clots. It is also well-known that therapeutic anticoagulation can place patients at a higher risk of bleeding. Thus, this unique population is at risk of developing both thrombotic and hemorrhagic events. We report a rare case of splenic infarction in a patient with confirmed COVID-19 infection despite prophylactic treatment with low-molecular-weight heparin which was found incidentally during workup for 2 other rare conditions: spontaneous rectus sheath hematoma and microhemorrhage or thrombus of the mesenteric vessels.
Introduction
In December 2019, the first cases of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported in Wuhan, China. Since, there have been 95,612,831 confirmed cases of COVID-19, including 2,066,176 deaths, reported to the World Health Organization [1]. Multiple studies have been done to examine clinical and epidemiologic aspects of the disease [2], [3], [4], [5], [6], [7]. It is well established that COVID-19 has a myriad of presentations, ranging from asymptomatic to severe illness; the most severe cases being observed in the elderly and those with comorbid conditions [8,9]. COVID-19 predominantly attacks the pulmonary system, and causes acute lung injury and diffuse alveolar damage, but it also has been shown to affect multiple systems in patients with and without comorbidities. Literature suggests that infection with COVID-19 provokes arterial and venous thrombotic events [10], and could be contributing to the multisystem damage. In an autopsy study done by Falasca et al histopathological hallmarks of widespread vascular injury were found in the liver, kidney, bone marrow, and spleen [3]. The exact mechanism causing these findings is not yet understood, but it is theorized to be a distinct process unique to the Sars-Cov-2 virus [10]. The current postulations attribute the pathophysiological mechanisms of COVID-19-related hypercoagulopathy to systemic inflammatory response syndrome (SIRS) precipitated by cytokine storm or activation of the coagulation cascade due to cellular activation triggered by the virus, or both [11]. These pathologies are quantified by measurement of the D-dimer and fibrin degradation product levels which have been shown to correlate with the severity of disease and patient prognosis [7].
Interestingly, the patient we present suffered one confirmed and one possible hemorrhagic event as a result of being anticoagulated to prevent further thrombus formation. 80 mg prophylactic LMWH was being administered twice daily, but the measured D-dimer remained markedly elevated. COVID-19-related hypercoagulopathy dictates that clinically-overt bleeding is uncommon in the setting of COVID-19 [12]. However, bleeding is a risk of therapeutic anticoagulation. Our patient spontaneously developed bilateral rectus sheath hematomas (RSH) as well as mesenteric vessel microhemorrhage. Rectus sheath hematoma is an uncommon cause of acute abdomen and can be benign, but in the setting of a patient receiving anticoagulation agents, can quickly progress to a life-threatening event. To date, there is only one other case reported of rectus sheath hematoma in a patient with COVID-19 [13]. Splenic infarct, mesenteric vessel infarct, and rectus sheath hematoma are rare in COVID-19 patients and providers should be aware of these potential complications. We present a case where all 3 are concurrently present in the same patient.
Narrative
A male in his 70s with a past medical history of hypertension, benign prostatic hypertrophy, gastroesophageal reflux disease, and depression presented to the emergency department with a chief complaint of worsening dyspnea. Seven days prior, the patient developed a dry cough with sore throat, and subsequently tested positive for COVID-19 which he had been managing at home on an outpatient basis. Since his COVID-19 diagnosis, his symptoms continued to worsen, and upon arrival to the emergency department he had dyspnea at rest, nonproductive cough, fevers, nausea, decreased appetite, and weakness. He was found to be in acute hypoxic respiratory failure with oxygen saturation (O2 SAT) of 68% on room air. His O2 SAT increased to 88%-92% on a 15% nonrebreather mask. He was also tachypneic at 22 breaths per minute and afebrile at 37.6 °C. Chest X-ray revealed new extensive patchy consolidative opacities about the lungs, favored to represent multifocal pneumonia. Laboratory evaluation was significant for elevated D-dimer, fibrinogen, and ferritin at 14.41 mg/L, 620 mg/dL and 1973 mg/mL, respectively. Additionally, lactic acid and white blood cell count were both elevated at 2.6 mmol/L and 14,900 cells/uL, respectively. Blood and urine cultures were negative. Treatment with enoxaparin, dexamethasone, and remdesivir was initiated as the patient was admitted to the intensive care unit for inpatient management of sepsis, viral pneumonia, severe COVID-19 infection, and acute hypoxic respiratory failure.
On hospital admission day 2, repeat D-dimer continued to be elevated at 5.56 ng/mL. A duplex ultrasound examination of the bilateral lower extremities was performed which revealed no evidence of intraluminal thrombus. Over the course of the next few days, the patient reported improved symptomatology and resolved dyspnea. His acute hypoxic respiratory failure was improving; he was reduced from 90% FiO2 on BiPAP to 45% FiO2, high-flow nasal cannula/BiPAP. His care was transferred from intensive care to intermediate care. His D-dimer continued to be elevated at 4.20, 3.78, and 4.58 ng/mL on hospital admission days 3, 4, and 5, respectively.
On the morning of hospital admission day 6, the patient continued to endorse improvement of symptoms, including no nausea, vomiting, fever, or chills, but he began to complain of constipation. To manage said constipation, the patient was given 30 mL oral lactulose for symptomatic relief.
Later that evening, the patient had a large bowel movement. Subsequently, the patient experienced acute onset of severe left lower quadrant abdominal pain. CT scan of the abdomen and pelvis with intravenous contrast revealed several findings. A 4 cm well-demarcated area of nonenhancement within the anterior superior spleen (Fig. 1) consistent with acute infarct was seen. Additionally, there was inflammation within fat surrounding the mesenteric vessels in the left upper quadrant (Fig. 2) which was suspected to be microhemorrhage or thrombosis. There were also large hematomas within the bilateral rectus muscles (Fig. 3, Fig. 4, Fig. 5) beginning just above the umbilicus extending down to the pubis measuring 5.6 cm × 18 cm on the left (Fig. 4) and 7 cm × 4 cm × 10 cm on the right (Figs. 4 and 5). Contrast within the hematomas suggested active bleeding at the time of imaging (Fig. 3). Hemoglobin was tested and was found to have decreased from 13.7 g/dL at the time of admission to 10.7 g/dL shortly after the time of CT scan. The patient's full dose enoxaparin, which was initially started due to significantly elevated D-dimer, was subsequently discontinued due to the presence of actively bleeding hematomas, despite the presence of a splenic infarct. When measured earlier that morning, his D-dimer continued to be elevated at 3.90 mg/mL.Fig. 1 Axial CT image of the abdomen demonstrating a 4 cm well-demarcated area of nonenhancement within the spleen on abdominal CT with IV contrast.
Fig 1
Fig. 2 Coronal abdominal CT image of the abdomen/pelvis demonstrating edema and fat stranding surrounding the left upper quadrant mesenteric vessels (red oval). This was thought to be due to mesenteric vessel microthrombi or hemorrhage. A definitive diagnosis was never established.
Fig. 2
Fig. 3 Axial CT image of the abdomen/pelvis demonstrating large hematomas within the bilateral rectus muscles (red arrows). Contrast within the left hematoma (red arrowhead) suggests active bleeding at the time of imaging. Dense fluid within the pelvis and along intrapelvic fascial planes is consistent with hemorrhage.
Fig. 3
Fig. 4 Sagittal CT images of the abdomen/pelvis with length measurement of the right and left rectus sheath hematomas.
Fig 4
Fig. 5 Axial CT image of the abdomen/pelvis with diameter measurements of the right rectus sheath hematoma.
Fig 5
At this time, the decision was made to transfer the patient by helicopter to a tertiary care center for possible interventional radiology embolization as well as management of the large rectus hematomas. At this point, the patient had received 6 doses of IV remdesevir out of 10 as well as 6 days of IV dexamethasone. The patient was stable at the time of transfer.
After 2 days of in-patient care at the tertiary center, it was determined that the active bleeding had stopped, and the hematomas remained stable. The patient's COVID-19 symptoms had also improved, and he was able to maintain adequate oxygenation levels while ambulating. The patient was discharged to complete his recovery at home. His recovery course has gone well without complications and as of 2 months following discharge he has been able to safely return to normal activity.
Discussion
COVID-19 infection is well known to cause hypercoagulability with pulmonary emboli being the most common presentation, splenic artery embolism and splenic infarction are rarely reported [14], [15], [16]. Splenic infarct is a rare cause of abdominal pain, often secondary to a hypercoagulable state [7]. COVID-19 hypercoagulability has been proposed to occur due to elevation of proinflammatory cytokines, including IL-6 [14], [15], [16]. Additionally, elevated D-dimer and fibrinogen degradation products are associated with poorer disease prognosis, potentially related to risk of disseminated intravascular coagulation [16]. Thus, treatment of the hypercoagulable state with antithrombotic agents is appropriate.
In a brief literature review, we identified 5 case studies consisting of 6 patients with involvement of splenic thromboembolism secondary to COVID-19 infection, including one case of atraumatic splenic rupture, and one case of hemoperitoneum [7,10,[17], [18], [19]. Additionally, multiple post-mortem autopsies have identified splenic involvement secondary to COVID-19 infection [2], [3], [4], [5], [6]. There have also been 2 cases of psoas hematoma [20,21]. As of yet, there has been only one prior report of rectus sheath hematoma secondary to COVID-19 coagulopathy [13].
Abdominal scans are not routinely performed in COVID-19 patients as primary symptomatology involves the respiratory tract. Thus, only symptomatic splenic infarctions or those found incidentally on CT scans of the chest extending into the abdomen may be identified. Evidence of splenic involvement has been noted on autopsy in patients known to have had COVID-19 [2], [3], [4], [5], [6]. This suggests that the presence of splenic involvement due to COVID-19 hypercoagulability may be higher than reported. While most cases of splenic infarct may be asymptomatic, atraumatic splenic rupture can be a devastating complication and necessitates a high clinical index of suspicion for patients with abdominal pain and concurrent or prior COVID-19 infection.
Rectus sheath hematoma is an uncommon complication of anticoagulation therapy. Other risk factors include old age, female gender, history of abdominal surgery/trauma/injections, cancer, coagulopathies, and renal impairment [22]. We hypothesize that the development of RSH in our patient was due to shearing of the epigastric vessels caused by the combination of anticoagulation therapy and trauma caused by straining and/or coughing. Early diagnosis and intervention are key to improving patient mortality and morbidity. CT scan with IV contrast is considered the gold standard [22], for identification of bleeding and for differentiating between arterial and venous bleeds [13] In cases where conservative management is unsuccessful, or the patient presents with severe clinical criteria, CT angiography can be utilized to identify active bleeding and help in staging for interventional radiology treatment [23]. In patients who have contraindication to contrast, Doppler ultrasound and red cell scintigraphy can be used. The required treatment should be dictated by the severity of the RSH and status of the patient. Conservative therapy including a binder, rest and analgesics may be adequate in the stable patient, whereas patients with hemodynamic instability may require resuscitation using IV fluids and blood products. In patients who have been anticoagulated, intravascular coil embolization or rarely surgery to ligate the epigastric vessels, may be required to achieve adequate hemostatic control.
Conclusion
Splenic infarction in COVID-19 infection is rarely reported and may go undetected if symptoms are vague or obscured by other ailments such as constipation, placing patients at risk of splenic rupture. Likewise, SRSH are also rare, a source for abdominal pain and a potentially serious condition especially in the anticoagulated patient, necessitating emergent treatment and the need to weigh the risks of hemorrhage versus thrombus when considering anticoagulation reversal. Despite their rarity, these conditions are treatable and should be considered in COVID-19 patients with abdominal pain and radiologists should monitor for thrombosis to aid in early diagnosis. Additionally, further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Learning points
• COVID-19 is well known to predispose patients for hypercoagulable events and complications, including thrombosis of unusual locations such as splenic artery branches.
• Anticoagulant management of acute thrombotic events in COVID-19 is critical in prevention of morbidity and mortality.
• Full anticoagulation predisposes patients to adverse effects related to bleeding and hemorrhage, including rectus sheath hematoma.
• There are no clear guidelines on management of hemorrhagic events in patients on therapeutic anticoagulation as treatment of ischemia due to thrombus, the risks of hemorrhage versus thrombosis must be weighed.
• Further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Patient consent statement
We are using entirely anonymized images from CT scans. These do not contain any identifying marks and are not accompanied by text that might identify the individual concerned.
Credit author statement
Jennifer Dennison: Writing-Original draft preparation and Editing, Investigation, Visualization: Samuel Carlson: Writing-Original draft preparation and Editing: Shannon Faehling: Writing-Original draft preparation and Editing: Hannah Phelan: Writing-Review and Editing: Muhammad Tariq: Writing-Review and Editing Ateeq Mubarik: Writing-Review and Editing, Supervision.
Institutional review board statement: Institutional Review Board approval was not necessary for our report.
Funding: None. The authors did not receive grant or outside funding in support of their research or preparation of this manuscript. They did not receive payment or any benefits from commercial entities.Declaration of competing interest
All authors declare that they have no competing interests. | DEXAMETHASONE, ENOXAPARIN, REMDESIVIR | DrugsGivenReaction | CC BY-NC-ND | 33619439 | 19,173,777 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage'. | Splenic infarction and spontaneous rectus sheath hematomas in COVID-19 patient.
Multiple studies and reports have suggested that coronavirus disease-19 (COVID-19) promotes arterial and venous thrombotic events in multiple organ systems, although the mechanism leading to a hypercoagulable state is still unknown. Few cases of splenic infarction associated with COVID-19 have been reported, of which half were found incidentally upon autopsy. This may be due to a clinically silent presentation or the symptoms being wrongfully attributed to pain caused by the effects of COVID-19. Due to the rarity of the condition and its lack of consistent symptomatology, splenic thromboembolism can be difficult to diagnose. Awareness of the condition and high clinical suspicion will help the clinician identify and manage the problem. Hemorrhage in patients with COVID-19 is uncommon in the hypercoagulable state that threatens thrombus formation in patients with COVID-19 infection. Despite prophylactic treatment with anticoagulation therapies, patients are more prone to developing clots. It is also well-known that therapeutic anticoagulation can place patients at a higher risk of bleeding. Thus, this unique population is at risk of developing both thrombotic and hemorrhagic events. We report a rare case of splenic infarction in a patient with confirmed COVID-19 infection despite prophylactic treatment with low-molecular-weight heparin which was found incidentally during workup for 2 other rare conditions: spontaneous rectus sheath hematoma and microhemorrhage or thrombus of the mesenteric vessels.
Introduction
In December 2019, the first cases of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported in Wuhan, China. Since, there have been 95,612,831 confirmed cases of COVID-19, including 2,066,176 deaths, reported to the World Health Organization [1]. Multiple studies have been done to examine clinical and epidemiologic aspects of the disease [2], [3], [4], [5], [6], [7]. It is well established that COVID-19 has a myriad of presentations, ranging from asymptomatic to severe illness; the most severe cases being observed in the elderly and those with comorbid conditions [8,9]. COVID-19 predominantly attacks the pulmonary system, and causes acute lung injury and diffuse alveolar damage, but it also has been shown to affect multiple systems in patients with and without comorbidities. Literature suggests that infection with COVID-19 provokes arterial and venous thrombotic events [10], and could be contributing to the multisystem damage. In an autopsy study done by Falasca et al histopathological hallmarks of widespread vascular injury were found in the liver, kidney, bone marrow, and spleen [3]. The exact mechanism causing these findings is not yet understood, but it is theorized to be a distinct process unique to the Sars-Cov-2 virus [10]. The current postulations attribute the pathophysiological mechanisms of COVID-19-related hypercoagulopathy to systemic inflammatory response syndrome (SIRS) precipitated by cytokine storm or activation of the coagulation cascade due to cellular activation triggered by the virus, or both [11]. These pathologies are quantified by measurement of the D-dimer and fibrin degradation product levels which have been shown to correlate with the severity of disease and patient prognosis [7].
Interestingly, the patient we present suffered one confirmed and one possible hemorrhagic event as a result of being anticoagulated to prevent further thrombus formation. 80 mg prophylactic LMWH was being administered twice daily, but the measured D-dimer remained markedly elevated. COVID-19-related hypercoagulopathy dictates that clinically-overt bleeding is uncommon in the setting of COVID-19 [12]. However, bleeding is a risk of therapeutic anticoagulation. Our patient spontaneously developed bilateral rectus sheath hematomas (RSH) as well as mesenteric vessel microhemorrhage. Rectus sheath hematoma is an uncommon cause of acute abdomen and can be benign, but in the setting of a patient receiving anticoagulation agents, can quickly progress to a life-threatening event. To date, there is only one other case reported of rectus sheath hematoma in a patient with COVID-19 [13]. Splenic infarct, mesenteric vessel infarct, and rectus sheath hematoma are rare in COVID-19 patients and providers should be aware of these potential complications. We present a case where all 3 are concurrently present in the same patient.
Narrative
A male in his 70s with a past medical history of hypertension, benign prostatic hypertrophy, gastroesophageal reflux disease, and depression presented to the emergency department with a chief complaint of worsening dyspnea. Seven days prior, the patient developed a dry cough with sore throat, and subsequently tested positive for COVID-19 which he had been managing at home on an outpatient basis. Since his COVID-19 diagnosis, his symptoms continued to worsen, and upon arrival to the emergency department he had dyspnea at rest, nonproductive cough, fevers, nausea, decreased appetite, and weakness. He was found to be in acute hypoxic respiratory failure with oxygen saturation (O2 SAT) of 68% on room air. His O2 SAT increased to 88%-92% on a 15% nonrebreather mask. He was also tachypneic at 22 breaths per minute and afebrile at 37.6 °C. Chest X-ray revealed new extensive patchy consolidative opacities about the lungs, favored to represent multifocal pneumonia. Laboratory evaluation was significant for elevated D-dimer, fibrinogen, and ferritin at 14.41 mg/L, 620 mg/dL and 1973 mg/mL, respectively. Additionally, lactic acid and white blood cell count were both elevated at 2.6 mmol/L and 14,900 cells/uL, respectively. Blood and urine cultures were negative. Treatment with enoxaparin, dexamethasone, and remdesivir was initiated as the patient was admitted to the intensive care unit for inpatient management of sepsis, viral pneumonia, severe COVID-19 infection, and acute hypoxic respiratory failure.
On hospital admission day 2, repeat D-dimer continued to be elevated at 5.56 ng/mL. A duplex ultrasound examination of the bilateral lower extremities was performed which revealed no evidence of intraluminal thrombus. Over the course of the next few days, the patient reported improved symptomatology and resolved dyspnea. His acute hypoxic respiratory failure was improving; he was reduced from 90% FiO2 on BiPAP to 45% FiO2, high-flow nasal cannula/BiPAP. His care was transferred from intensive care to intermediate care. His D-dimer continued to be elevated at 4.20, 3.78, and 4.58 ng/mL on hospital admission days 3, 4, and 5, respectively.
On the morning of hospital admission day 6, the patient continued to endorse improvement of symptoms, including no nausea, vomiting, fever, or chills, but he began to complain of constipation. To manage said constipation, the patient was given 30 mL oral lactulose for symptomatic relief.
Later that evening, the patient had a large bowel movement. Subsequently, the patient experienced acute onset of severe left lower quadrant abdominal pain. CT scan of the abdomen and pelvis with intravenous contrast revealed several findings. A 4 cm well-demarcated area of nonenhancement within the anterior superior spleen (Fig. 1) consistent with acute infarct was seen. Additionally, there was inflammation within fat surrounding the mesenteric vessels in the left upper quadrant (Fig. 2) which was suspected to be microhemorrhage or thrombosis. There were also large hematomas within the bilateral rectus muscles (Fig. 3, Fig. 4, Fig. 5) beginning just above the umbilicus extending down to the pubis measuring 5.6 cm × 18 cm on the left (Fig. 4) and 7 cm × 4 cm × 10 cm on the right (Figs. 4 and 5). Contrast within the hematomas suggested active bleeding at the time of imaging (Fig. 3). Hemoglobin was tested and was found to have decreased from 13.7 g/dL at the time of admission to 10.7 g/dL shortly after the time of CT scan. The patient's full dose enoxaparin, which was initially started due to significantly elevated D-dimer, was subsequently discontinued due to the presence of actively bleeding hematomas, despite the presence of a splenic infarct. When measured earlier that morning, his D-dimer continued to be elevated at 3.90 mg/mL.Fig. 1 Axial CT image of the abdomen demonstrating a 4 cm well-demarcated area of nonenhancement within the spleen on abdominal CT with IV contrast.
Fig 1
Fig. 2 Coronal abdominal CT image of the abdomen/pelvis demonstrating edema and fat stranding surrounding the left upper quadrant mesenteric vessels (red oval). This was thought to be due to mesenteric vessel microthrombi or hemorrhage. A definitive diagnosis was never established.
Fig. 2
Fig. 3 Axial CT image of the abdomen/pelvis demonstrating large hematomas within the bilateral rectus muscles (red arrows). Contrast within the left hematoma (red arrowhead) suggests active bleeding at the time of imaging. Dense fluid within the pelvis and along intrapelvic fascial planes is consistent with hemorrhage.
Fig. 3
Fig. 4 Sagittal CT images of the abdomen/pelvis with length measurement of the right and left rectus sheath hematomas.
Fig 4
Fig. 5 Axial CT image of the abdomen/pelvis with diameter measurements of the right rectus sheath hematoma.
Fig 5
At this time, the decision was made to transfer the patient by helicopter to a tertiary care center for possible interventional radiology embolization as well as management of the large rectus hematomas. At this point, the patient had received 6 doses of IV remdesevir out of 10 as well as 6 days of IV dexamethasone. The patient was stable at the time of transfer.
After 2 days of in-patient care at the tertiary center, it was determined that the active bleeding had stopped, and the hematomas remained stable. The patient's COVID-19 symptoms had also improved, and he was able to maintain adequate oxygenation levels while ambulating. The patient was discharged to complete his recovery at home. His recovery course has gone well without complications and as of 2 months following discharge he has been able to safely return to normal activity.
Discussion
COVID-19 infection is well known to cause hypercoagulability with pulmonary emboli being the most common presentation, splenic artery embolism and splenic infarction are rarely reported [14], [15], [16]. Splenic infarct is a rare cause of abdominal pain, often secondary to a hypercoagulable state [7]. COVID-19 hypercoagulability has been proposed to occur due to elevation of proinflammatory cytokines, including IL-6 [14], [15], [16]. Additionally, elevated D-dimer and fibrinogen degradation products are associated with poorer disease prognosis, potentially related to risk of disseminated intravascular coagulation [16]. Thus, treatment of the hypercoagulable state with antithrombotic agents is appropriate.
In a brief literature review, we identified 5 case studies consisting of 6 patients with involvement of splenic thromboembolism secondary to COVID-19 infection, including one case of atraumatic splenic rupture, and one case of hemoperitoneum [7,10,[17], [18], [19]. Additionally, multiple post-mortem autopsies have identified splenic involvement secondary to COVID-19 infection [2], [3], [4], [5], [6]. There have also been 2 cases of psoas hematoma [20,21]. As of yet, there has been only one prior report of rectus sheath hematoma secondary to COVID-19 coagulopathy [13].
Abdominal scans are not routinely performed in COVID-19 patients as primary symptomatology involves the respiratory tract. Thus, only symptomatic splenic infarctions or those found incidentally on CT scans of the chest extending into the abdomen may be identified. Evidence of splenic involvement has been noted on autopsy in patients known to have had COVID-19 [2], [3], [4], [5], [6]. This suggests that the presence of splenic involvement due to COVID-19 hypercoagulability may be higher than reported. While most cases of splenic infarct may be asymptomatic, atraumatic splenic rupture can be a devastating complication and necessitates a high clinical index of suspicion for patients with abdominal pain and concurrent or prior COVID-19 infection.
Rectus sheath hematoma is an uncommon complication of anticoagulation therapy. Other risk factors include old age, female gender, history of abdominal surgery/trauma/injections, cancer, coagulopathies, and renal impairment [22]. We hypothesize that the development of RSH in our patient was due to shearing of the epigastric vessels caused by the combination of anticoagulation therapy and trauma caused by straining and/or coughing. Early diagnosis and intervention are key to improving patient mortality and morbidity. CT scan with IV contrast is considered the gold standard [22], for identification of bleeding and for differentiating between arterial and venous bleeds [13] In cases where conservative management is unsuccessful, or the patient presents with severe clinical criteria, CT angiography can be utilized to identify active bleeding and help in staging for interventional radiology treatment [23]. In patients who have contraindication to contrast, Doppler ultrasound and red cell scintigraphy can be used. The required treatment should be dictated by the severity of the RSH and status of the patient. Conservative therapy including a binder, rest and analgesics may be adequate in the stable patient, whereas patients with hemodynamic instability may require resuscitation using IV fluids and blood products. In patients who have been anticoagulated, intravascular coil embolization or rarely surgery to ligate the epigastric vessels, may be required to achieve adequate hemostatic control.
Conclusion
Splenic infarction in COVID-19 infection is rarely reported and may go undetected if symptoms are vague or obscured by other ailments such as constipation, placing patients at risk of splenic rupture. Likewise, SRSH are also rare, a source for abdominal pain and a potentially serious condition especially in the anticoagulated patient, necessitating emergent treatment and the need to weigh the risks of hemorrhage versus thrombus when considering anticoagulation reversal. Despite their rarity, these conditions are treatable and should be considered in COVID-19 patients with abdominal pain and radiologists should monitor for thrombosis to aid in early diagnosis. Additionally, further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Learning points
• COVID-19 is well known to predispose patients for hypercoagulable events and complications, including thrombosis of unusual locations such as splenic artery branches.
• Anticoagulant management of acute thrombotic events in COVID-19 is critical in prevention of morbidity and mortality.
• Full anticoagulation predisposes patients to adverse effects related to bleeding and hemorrhage, including rectus sheath hematoma.
• There are no clear guidelines on management of hemorrhagic events in patients on therapeutic anticoagulation as treatment of ischemia due to thrombus, the risks of hemorrhage versus thrombosis must be weighed.
• Further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Patient consent statement
We are using entirely anonymized images from CT scans. These do not contain any identifying marks and are not accompanied by text that might identify the individual concerned.
Credit author statement
Jennifer Dennison: Writing-Original draft preparation and Editing, Investigation, Visualization: Samuel Carlson: Writing-Original draft preparation and Editing: Shannon Faehling: Writing-Original draft preparation and Editing: Hannah Phelan: Writing-Review and Editing: Muhammad Tariq: Writing-Review and Editing Ateeq Mubarik: Writing-Review and Editing, Supervision.
Institutional review board statement: Institutional Review Board approval was not necessary for our report.
Funding: None. The authors did not receive grant or outside funding in support of their research or preparation of this manuscript. They did not receive payment or any benefits from commercial entities.Declaration of competing interest
All authors declare that they have no competing interests. | DEXAMETHASONE, ENOXAPARIN, REMDESIVIR | DrugsGivenReaction | CC BY-NC-ND | 33619439 | 19,173,777 | 2021-05 |
What was the administration route of drug 'DEXAMETHASONE'? | Splenic infarction and spontaneous rectus sheath hematomas in COVID-19 patient.
Multiple studies and reports have suggested that coronavirus disease-19 (COVID-19) promotes arterial and venous thrombotic events in multiple organ systems, although the mechanism leading to a hypercoagulable state is still unknown. Few cases of splenic infarction associated with COVID-19 have been reported, of which half were found incidentally upon autopsy. This may be due to a clinically silent presentation or the symptoms being wrongfully attributed to pain caused by the effects of COVID-19. Due to the rarity of the condition and its lack of consistent symptomatology, splenic thromboembolism can be difficult to diagnose. Awareness of the condition and high clinical suspicion will help the clinician identify and manage the problem. Hemorrhage in patients with COVID-19 is uncommon in the hypercoagulable state that threatens thrombus formation in patients with COVID-19 infection. Despite prophylactic treatment with anticoagulation therapies, patients are more prone to developing clots. It is also well-known that therapeutic anticoagulation can place patients at a higher risk of bleeding. Thus, this unique population is at risk of developing both thrombotic and hemorrhagic events. We report a rare case of splenic infarction in a patient with confirmed COVID-19 infection despite prophylactic treatment with low-molecular-weight heparin which was found incidentally during workup for 2 other rare conditions: spontaneous rectus sheath hematoma and microhemorrhage or thrombus of the mesenteric vessels.
Introduction
In December 2019, the first cases of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported in Wuhan, China. Since, there have been 95,612,831 confirmed cases of COVID-19, including 2,066,176 deaths, reported to the World Health Organization [1]. Multiple studies have been done to examine clinical and epidemiologic aspects of the disease [2], [3], [4], [5], [6], [7]. It is well established that COVID-19 has a myriad of presentations, ranging from asymptomatic to severe illness; the most severe cases being observed in the elderly and those with comorbid conditions [8,9]. COVID-19 predominantly attacks the pulmonary system, and causes acute lung injury and diffuse alveolar damage, but it also has been shown to affect multiple systems in patients with and without comorbidities. Literature suggests that infection with COVID-19 provokes arterial and venous thrombotic events [10], and could be contributing to the multisystem damage. In an autopsy study done by Falasca et al histopathological hallmarks of widespread vascular injury were found in the liver, kidney, bone marrow, and spleen [3]. The exact mechanism causing these findings is not yet understood, but it is theorized to be a distinct process unique to the Sars-Cov-2 virus [10]. The current postulations attribute the pathophysiological mechanisms of COVID-19-related hypercoagulopathy to systemic inflammatory response syndrome (SIRS) precipitated by cytokine storm or activation of the coagulation cascade due to cellular activation triggered by the virus, or both [11]. These pathologies are quantified by measurement of the D-dimer and fibrin degradation product levels which have been shown to correlate with the severity of disease and patient prognosis [7].
Interestingly, the patient we present suffered one confirmed and one possible hemorrhagic event as a result of being anticoagulated to prevent further thrombus formation. 80 mg prophylactic LMWH was being administered twice daily, but the measured D-dimer remained markedly elevated. COVID-19-related hypercoagulopathy dictates that clinically-overt bleeding is uncommon in the setting of COVID-19 [12]. However, bleeding is a risk of therapeutic anticoagulation. Our patient spontaneously developed bilateral rectus sheath hematomas (RSH) as well as mesenteric vessel microhemorrhage. Rectus sheath hematoma is an uncommon cause of acute abdomen and can be benign, but in the setting of a patient receiving anticoagulation agents, can quickly progress to a life-threatening event. To date, there is only one other case reported of rectus sheath hematoma in a patient with COVID-19 [13]. Splenic infarct, mesenteric vessel infarct, and rectus sheath hematoma are rare in COVID-19 patients and providers should be aware of these potential complications. We present a case where all 3 are concurrently present in the same patient.
Narrative
A male in his 70s with a past medical history of hypertension, benign prostatic hypertrophy, gastroesophageal reflux disease, and depression presented to the emergency department with a chief complaint of worsening dyspnea. Seven days prior, the patient developed a dry cough with sore throat, and subsequently tested positive for COVID-19 which he had been managing at home on an outpatient basis. Since his COVID-19 diagnosis, his symptoms continued to worsen, and upon arrival to the emergency department he had dyspnea at rest, nonproductive cough, fevers, nausea, decreased appetite, and weakness. He was found to be in acute hypoxic respiratory failure with oxygen saturation (O2 SAT) of 68% on room air. His O2 SAT increased to 88%-92% on a 15% nonrebreather mask. He was also tachypneic at 22 breaths per minute and afebrile at 37.6 °C. Chest X-ray revealed new extensive patchy consolidative opacities about the lungs, favored to represent multifocal pneumonia. Laboratory evaluation was significant for elevated D-dimer, fibrinogen, and ferritin at 14.41 mg/L, 620 mg/dL and 1973 mg/mL, respectively. Additionally, lactic acid and white blood cell count were both elevated at 2.6 mmol/L and 14,900 cells/uL, respectively. Blood and urine cultures were negative. Treatment with enoxaparin, dexamethasone, and remdesivir was initiated as the patient was admitted to the intensive care unit for inpatient management of sepsis, viral pneumonia, severe COVID-19 infection, and acute hypoxic respiratory failure.
On hospital admission day 2, repeat D-dimer continued to be elevated at 5.56 ng/mL. A duplex ultrasound examination of the bilateral lower extremities was performed which revealed no evidence of intraluminal thrombus. Over the course of the next few days, the patient reported improved symptomatology and resolved dyspnea. His acute hypoxic respiratory failure was improving; he was reduced from 90% FiO2 on BiPAP to 45% FiO2, high-flow nasal cannula/BiPAP. His care was transferred from intensive care to intermediate care. His D-dimer continued to be elevated at 4.20, 3.78, and 4.58 ng/mL on hospital admission days 3, 4, and 5, respectively.
On the morning of hospital admission day 6, the patient continued to endorse improvement of symptoms, including no nausea, vomiting, fever, or chills, but he began to complain of constipation. To manage said constipation, the patient was given 30 mL oral lactulose for symptomatic relief.
Later that evening, the patient had a large bowel movement. Subsequently, the patient experienced acute onset of severe left lower quadrant abdominal pain. CT scan of the abdomen and pelvis with intravenous contrast revealed several findings. A 4 cm well-demarcated area of nonenhancement within the anterior superior spleen (Fig. 1) consistent with acute infarct was seen. Additionally, there was inflammation within fat surrounding the mesenteric vessels in the left upper quadrant (Fig. 2) which was suspected to be microhemorrhage or thrombosis. There were also large hematomas within the bilateral rectus muscles (Fig. 3, Fig. 4, Fig. 5) beginning just above the umbilicus extending down to the pubis measuring 5.6 cm × 18 cm on the left (Fig. 4) and 7 cm × 4 cm × 10 cm on the right (Figs. 4 and 5). Contrast within the hematomas suggested active bleeding at the time of imaging (Fig. 3). Hemoglobin was tested and was found to have decreased from 13.7 g/dL at the time of admission to 10.7 g/dL shortly after the time of CT scan. The patient's full dose enoxaparin, which was initially started due to significantly elevated D-dimer, was subsequently discontinued due to the presence of actively bleeding hematomas, despite the presence of a splenic infarct. When measured earlier that morning, his D-dimer continued to be elevated at 3.90 mg/mL.Fig. 1 Axial CT image of the abdomen demonstrating a 4 cm well-demarcated area of nonenhancement within the spleen on abdominal CT with IV contrast.
Fig 1
Fig. 2 Coronal abdominal CT image of the abdomen/pelvis demonstrating edema and fat stranding surrounding the left upper quadrant mesenteric vessels (red oval). This was thought to be due to mesenteric vessel microthrombi or hemorrhage. A definitive diagnosis was never established.
Fig. 2
Fig. 3 Axial CT image of the abdomen/pelvis demonstrating large hematomas within the bilateral rectus muscles (red arrows). Contrast within the left hematoma (red arrowhead) suggests active bleeding at the time of imaging. Dense fluid within the pelvis and along intrapelvic fascial planes is consistent with hemorrhage.
Fig. 3
Fig. 4 Sagittal CT images of the abdomen/pelvis with length measurement of the right and left rectus sheath hematomas.
Fig 4
Fig. 5 Axial CT image of the abdomen/pelvis with diameter measurements of the right rectus sheath hematoma.
Fig 5
At this time, the decision was made to transfer the patient by helicopter to a tertiary care center for possible interventional radiology embolization as well as management of the large rectus hematomas. At this point, the patient had received 6 doses of IV remdesevir out of 10 as well as 6 days of IV dexamethasone. The patient was stable at the time of transfer.
After 2 days of in-patient care at the tertiary center, it was determined that the active bleeding had stopped, and the hematomas remained stable. The patient's COVID-19 symptoms had also improved, and he was able to maintain adequate oxygenation levels while ambulating. The patient was discharged to complete his recovery at home. His recovery course has gone well without complications and as of 2 months following discharge he has been able to safely return to normal activity.
Discussion
COVID-19 infection is well known to cause hypercoagulability with pulmonary emboli being the most common presentation, splenic artery embolism and splenic infarction are rarely reported [14], [15], [16]. Splenic infarct is a rare cause of abdominal pain, often secondary to a hypercoagulable state [7]. COVID-19 hypercoagulability has been proposed to occur due to elevation of proinflammatory cytokines, including IL-6 [14], [15], [16]. Additionally, elevated D-dimer and fibrinogen degradation products are associated with poorer disease prognosis, potentially related to risk of disseminated intravascular coagulation [16]. Thus, treatment of the hypercoagulable state with antithrombotic agents is appropriate.
In a brief literature review, we identified 5 case studies consisting of 6 patients with involvement of splenic thromboembolism secondary to COVID-19 infection, including one case of atraumatic splenic rupture, and one case of hemoperitoneum [7,10,[17], [18], [19]. Additionally, multiple post-mortem autopsies have identified splenic involvement secondary to COVID-19 infection [2], [3], [4], [5], [6]. There have also been 2 cases of psoas hematoma [20,21]. As of yet, there has been only one prior report of rectus sheath hematoma secondary to COVID-19 coagulopathy [13].
Abdominal scans are not routinely performed in COVID-19 patients as primary symptomatology involves the respiratory tract. Thus, only symptomatic splenic infarctions or those found incidentally on CT scans of the chest extending into the abdomen may be identified. Evidence of splenic involvement has been noted on autopsy in patients known to have had COVID-19 [2], [3], [4], [5], [6]. This suggests that the presence of splenic involvement due to COVID-19 hypercoagulability may be higher than reported. While most cases of splenic infarct may be asymptomatic, atraumatic splenic rupture can be a devastating complication and necessitates a high clinical index of suspicion for patients with abdominal pain and concurrent or prior COVID-19 infection.
Rectus sheath hematoma is an uncommon complication of anticoagulation therapy. Other risk factors include old age, female gender, history of abdominal surgery/trauma/injections, cancer, coagulopathies, and renal impairment [22]. We hypothesize that the development of RSH in our patient was due to shearing of the epigastric vessels caused by the combination of anticoagulation therapy and trauma caused by straining and/or coughing. Early diagnosis and intervention are key to improving patient mortality and morbidity. CT scan with IV contrast is considered the gold standard [22], for identification of bleeding and for differentiating between arterial and venous bleeds [13] In cases where conservative management is unsuccessful, or the patient presents with severe clinical criteria, CT angiography can be utilized to identify active bleeding and help in staging for interventional radiology treatment [23]. In patients who have contraindication to contrast, Doppler ultrasound and red cell scintigraphy can be used. The required treatment should be dictated by the severity of the RSH and status of the patient. Conservative therapy including a binder, rest and analgesics may be adequate in the stable patient, whereas patients with hemodynamic instability may require resuscitation using IV fluids and blood products. In patients who have been anticoagulated, intravascular coil embolization or rarely surgery to ligate the epigastric vessels, may be required to achieve adequate hemostatic control.
Conclusion
Splenic infarction in COVID-19 infection is rarely reported and may go undetected if symptoms are vague or obscured by other ailments such as constipation, placing patients at risk of splenic rupture. Likewise, SRSH are also rare, a source for abdominal pain and a potentially serious condition especially in the anticoagulated patient, necessitating emergent treatment and the need to weigh the risks of hemorrhage versus thrombus when considering anticoagulation reversal. Despite their rarity, these conditions are treatable and should be considered in COVID-19 patients with abdominal pain and radiologists should monitor for thrombosis to aid in early diagnosis. Additionally, further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Learning points
• COVID-19 is well known to predispose patients for hypercoagulable events and complications, including thrombosis of unusual locations such as splenic artery branches.
• Anticoagulant management of acute thrombotic events in COVID-19 is critical in prevention of morbidity and mortality.
• Full anticoagulation predisposes patients to adverse effects related to bleeding and hemorrhage, including rectus sheath hematoma.
• There are no clear guidelines on management of hemorrhagic events in patients on therapeutic anticoagulation as treatment of ischemia due to thrombus, the risks of hemorrhage versus thrombosis must be weighed.
• Further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Patient consent statement
We are using entirely anonymized images from CT scans. These do not contain any identifying marks and are not accompanied by text that might identify the individual concerned.
Credit author statement
Jennifer Dennison: Writing-Original draft preparation and Editing, Investigation, Visualization: Samuel Carlson: Writing-Original draft preparation and Editing: Shannon Faehling: Writing-Original draft preparation and Editing: Hannah Phelan: Writing-Review and Editing: Muhammad Tariq: Writing-Review and Editing Ateeq Mubarik: Writing-Review and Editing, Supervision.
Institutional review board statement: Institutional Review Board approval was not necessary for our report.
Funding: None. The authors did not receive grant or outside funding in support of their research or preparation of this manuscript. They did not receive payment or any benefits from commercial entities.Declaration of competing interest
All authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33619439 | 19,173,777 | 2021-05 |
What was the administration route of drug 'REMDESIVIR'? | Splenic infarction and spontaneous rectus sheath hematomas in COVID-19 patient.
Multiple studies and reports have suggested that coronavirus disease-19 (COVID-19) promotes arterial and venous thrombotic events in multiple organ systems, although the mechanism leading to a hypercoagulable state is still unknown. Few cases of splenic infarction associated with COVID-19 have been reported, of which half were found incidentally upon autopsy. This may be due to a clinically silent presentation or the symptoms being wrongfully attributed to pain caused by the effects of COVID-19. Due to the rarity of the condition and its lack of consistent symptomatology, splenic thromboembolism can be difficult to diagnose. Awareness of the condition and high clinical suspicion will help the clinician identify and manage the problem. Hemorrhage in patients with COVID-19 is uncommon in the hypercoagulable state that threatens thrombus formation in patients with COVID-19 infection. Despite prophylactic treatment with anticoagulation therapies, patients are more prone to developing clots. It is also well-known that therapeutic anticoagulation can place patients at a higher risk of bleeding. Thus, this unique population is at risk of developing both thrombotic and hemorrhagic events. We report a rare case of splenic infarction in a patient with confirmed COVID-19 infection despite prophylactic treatment with low-molecular-weight heparin which was found incidentally during workup for 2 other rare conditions: spontaneous rectus sheath hematoma and microhemorrhage or thrombus of the mesenteric vessels.
Introduction
In December 2019, the first cases of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported in Wuhan, China. Since, there have been 95,612,831 confirmed cases of COVID-19, including 2,066,176 deaths, reported to the World Health Organization [1]. Multiple studies have been done to examine clinical and epidemiologic aspects of the disease [2], [3], [4], [5], [6], [7]. It is well established that COVID-19 has a myriad of presentations, ranging from asymptomatic to severe illness; the most severe cases being observed in the elderly and those with comorbid conditions [8,9]. COVID-19 predominantly attacks the pulmonary system, and causes acute lung injury and diffuse alveolar damage, but it also has been shown to affect multiple systems in patients with and without comorbidities. Literature suggests that infection with COVID-19 provokes arterial and venous thrombotic events [10], and could be contributing to the multisystem damage. In an autopsy study done by Falasca et al histopathological hallmarks of widespread vascular injury were found in the liver, kidney, bone marrow, and spleen [3]. The exact mechanism causing these findings is not yet understood, but it is theorized to be a distinct process unique to the Sars-Cov-2 virus [10]. The current postulations attribute the pathophysiological mechanisms of COVID-19-related hypercoagulopathy to systemic inflammatory response syndrome (SIRS) precipitated by cytokine storm or activation of the coagulation cascade due to cellular activation triggered by the virus, or both [11]. These pathologies are quantified by measurement of the D-dimer and fibrin degradation product levels which have been shown to correlate with the severity of disease and patient prognosis [7].
Interestingly, the patient we present suffered one confirmed and one possible hemorrhagic event as a result of being anticoagulated to prevent further thrombus formation. 80 mg prophylactic LMWH was being administered twice daily, but the measured D-dimer remained markedly elevated. COVID-19-related hypercoagulopathy dictates that clinically-overt bleeding is uncommon in the setting of COVID-19 [12]. However, bleeding is a risk of therapeutic anticoagulation. Our patient spontaneously developed bilateral rectus sheath hematomas (RSH) as well as mesenteric vessel microhemorrhage. Rectus sheath hematoma is an uncommon cause of acute abdomen and can be benign, but in the setting of a patient receiving anticoagulation agents, can quickly progress to a life-threatening event. To date, there is only one other case reported of rectus sheath hematoma in a patient with COVID-19 [13]. Splenic infarct, mesenteric vessel infarct, and rectus sheath hematoma are rare in COVID-19 patients and providers should be aware of these potential complications. We present a case where all 3 are concurrently present in the same patient.
Narrative
A male in his 70s with a past medical history of hypertension, benign prostatic hypertrophy, gastroesophageal reflux disease, and depression presented to the emergency department with a chief complaint of worsening dyspnea. Seven days prior, the patient developed a dry cough with sore throat, and subsequently tested positive for COVID-19 which he had been managing at home on an outpatient basis. Since his COVID-19 diagnosis, his symptoms continued to worsen, and upon arrival to the emergency department he had dyspnea at rest, nonproductive cough, fevers, nausea, decreased appetite, and weakness. He was found to be in acute hypoxic respiratory failure with oxygen saturation (O2 SAT) of 68% on room air. His O2 SAT increased to 88%-92% on a 15% nonrebreather mask. He was also tachypneic at 22 breaths per minute and afebrile at 37.6 °C. Chest X-ray revealed new extensive patchy consolidative opacities about the lungs, favored to represent multifocal pneumonia. Laboratory evaluation was significant for elevated D-dimer, fibrinogen, and ferritin at 14.41 mg/L, 620 mg/dL and 1973 mg/mL, respectively. Additionally, lactic acid and white blood cell count were both elevated at 2.6 mmol/L and 14,900 cells/uL, respectively. Blood and urine cultures were negative. Treatment with enoxaparin, dexamethasone, and remdesivir was initiated as the patient was admitted to the intensive care unit for inpatient management of sepsis, viral pneumonia, severe COVID-19 infection, and acute hypoxic respiratory failure.
On hospital admission day 2, repeat D-dimer continued to be elevated at 5.56 ng/mL. A duplex ultrasound examination of the bilateral lower extremities was performed which revealed no evidence of intraluminal thrombus. Over the course of the next few days, the patient reported improved symptomatology and resolved dyspnea. His acute hypoxic respiratory failure was improving; he was reduced from 90% FiO2 on BiPAP to 45% FiO2, high-flow nasal cannula/BiPAP. His care was transferred from intensive care to intermediate care. His D-dimer continued to be elevated at 4.20, 3.78, and 4.58 ng/mL on hospital admission days 3, 4, and 5, respectively.
On the morning of hospital admission day 6, the patient continued to endorse improvement of symptoms, including no nausea, vomiting, fever, or chills, but he began to complain of constipation. To manage said constipation, the patient was given 30 mL oral lactulose for symptomatic relief.
Later that evening, the patient had a large bowel movement. Subsequently, the patient experienced acute onset of severe left lower quadrant abdominal pain. CT scan of the abdomen and pelvis with intravenous contrast revealed several findings. A 4 cm well-demarcated area of nonenhancement within the anterior superior spleen (Fig. 1) consistent with acute infarct was seen. Additionally, there was inflammation within fat surrounding the mesenteric vessels in the left upper quadrant (Fig. 2) which was suspected to be microhemorrhage or thrombosis. There were also large hematomas within the bilateral rectus muscles (Fig. 3, Fig. 4, Fig. 5) beginning just above the umbilicus extending down to the pubis measuring 5.6 cm × 18 cm on the left (Fig. 4) and 7 cm × 4 cm × 10 cm on the right (Figs. 4 and 5). Contrast within the hematomas suggested active bleeding at the time of imaging (Fig. 3). Hemoglobin was tested and was found to have decreased from 13.7 g/dL at the time of admission to 10.7 g/dL shortly after the time of CT scan. The patient's full dose enoxaparin, which was initially started due to significantly elevated D-dimer, was subsequently discontinued due to the presence of actively bleeding hematomas, despite the presence of a splenic infarct. When measured earlier that morning, his D-dimer continued to be elevated at 3.90 mg/mL.Fig. 1 Axial CT image of the abdomen demonstrating a 4 cm well-demarcated area of nonenhancement within the spleen on abdominal CT with IV contrast.
Fig 1
Fig. 2 Coronal abdominal CT image of the abdomen/pelvis demonstrating edema and fat stranding surrounding the left upper quadrant mesenteric vessels (red oval). This was thought to be due to mesenteric vessel microthrombi or hemorrhage. A definitive diagnosis was never established.
Fig. 2
Fig. 3 Axial CT image of the abdomen/pelvis demonstrating large hematomas within the bilateral rectus muscles (red arrows). Contrast within the left hematoma (red arrowhead) suggests active bleeding at the time of imaging. Dense fluid within the pelvis and along intrapelvic fascial planes is consistent with hemorrhage.
Fig. 3
Fig. 4 Sagittal CT images of the abdomen/pelvis with length measurement of the right and left rectus sheath hematomas.
Fig 4
Fig. 5 Axial CT image of the abdomen/pelvis with diameter measurements of the right rectus sheath hematoma.
Fig 5
At this time, the decision was made to transfer the patient by helicopter to a tertiary care center for possible interventional radiology embolization as well as management of the large rectus hematomas. At this point, the patient had received 6 doses of IV remdesevir out of 10 as well as 6 days of IV dexamethasone. The patient was stable at the time of transfer.
After 2 days of in-patient care at the tertiary center, it was determined that the active bleeding had stopped, and the hematomas remained stable. The patient's COVID-19 symptoms had also improved, and he was able to maintain adequate oxygenation levels while ambulating. The patient was discharged to complete his recovery at home. His recovery course has gone well without complications and as of 2 months following discharge he has been able to safely return to normal activity.
Discussion
COVID-19 infection is well known to cause hypercoagulability with pulmonary emboli being the most common presentation, splenic artery embolism and splenic infarction are rarely reported [14], [15], [16]. Splenic infarct is a rare cause of abdominal pain, often secondary to a hypercoagulable state [7]. COVID-19 hypercoagulability has been proposed to occur due to elevation of proinflammatory cytokines, including IL-6 [14], [15], [16]. Additionally, elevated D-dimer and fibrinogen degradation products are associated with poorer disease prognosis, potentially related to risk of disseminated intravascular coagulation [16]. Thus, treatment of the hypercoagulable state with antithrombotic agents is appropriate.
In a brief literature review, we identified 5 case studies consisting of 6 patients with involvement of splenic thromboembolism secondary to COVID-19 infection, including one case of atraumatic splenic rupture, and one case of hemoperitoneum [7,10,[17], [18], [19]. Additionally, multiple post-mortem autopsies have identified splenic involvement secondary to COVID-19 infection [2], [3], [4], [5], [6]. There have also been 2 cases of psoas hematoma [20,21]. As of yet, there has been only one prior report of rectus sheath hematoma secondary to COVID-19 coagulopathy [13].
Abdominal scans are not routinely performed in COVID-19 patients as primary symptomatology involves the respiratory tract. Thus, only symptomatic splenic infarctions or those found incidentally on CT scans of the chest extending into the abdomen may be identified. Evidence of splenic involvement has been noted on autopsy in patients known to have had COVID-19 [2], [3], [4], [5], [6]. This suggests that the presence of splenic involvement due to COVID-19 hypercoagulability may be higher than reported. While most cases of splenic infarct may be asymptomatic, atraumatic splenic rupture can be a devastating complication and necessitates a high clinical index of suspicion for patients with abdominal pain and concurrent or prior COVID-19 infection.
Rectus sheath hematoma is an uncommon complication of anticoagulation therapy. Other risk factors include old age, female gender, history of abdominal surgery/trauma/injections, cancer, coagulopathies, and renal impairment [22]. We hypothesize that the development of RSH in our patient was due to shearing of the epigastric vessels caused by the combination of anticoagulation therapy and trauma caused by straining and/or coughing. Early diagnosis and intervention are key to improving patient mortality and morbidity. CT scan with IV contrast is considered the gold standard [22], for identification of bleeding and for differentiating between arterial and venous bleeds [13] In cases where conservative management is unsuccessful, or the patient presents with severe clinical criteria, CT angiography can be utilized to identify active bleeding and help in staging for interventional radiology treatment [23]. In patients who have contraindication to contrast, Doppler ultrasound and red cell scintigraphy can be used. The required treatment should be dictated by the severity of the RSH and status of the patient. Conservative therapy including a binder, rest and analgesics may be adequate in the stable patient, whereas patients with hemodynamic instability may require resuscitation using IV fluids and blood products. In patients who have been anticoagulated, intravascular coil embolization or rarely surgery to ligate the epigastric vessels, may be required to achieve adequate hemostatic control.
Conclusion
Splenic infarction in COVID-19 infection is rarely reported and may go undetected if symptoms are vague or obscured by other ailments such as constipation, placing patients at risk of splenic rupture. Likewise, SRSH are also rare, a source for abdominal pain and a potentially serious condition especially in the anticoagulated patient, necessitating emergent treatment and the need to weigh the risks of hemorrhage versus thrombus when considering anticoagulation reversal. Despite their rarity, these conditions are treatable and should be considered in COVID-19 patients with abdominal pain and radiologists should monitor for thrombosis to aid in early diagnosis. Additionally, further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Learning points
• COVID-19 is well known to predispose patients for hypercoagulable events and complications, including thrombosis of unusual locations such as splenic artery branches.
• Anticoagulant management of acute thrombotic events in COVID-19 is critical in prevention of morbidity and mortality.
• Full anticoagulation predisposes patients to adverse effects related to bleeding and hemorrhage, including rectus sheath hematoma.
• There are no clear guidelines on management of hemorrhagic events in patients on therapeutic anticoagulation as treatment of ischemia due to thrombus, the risks of hemorrhage versus thrombosis must be weighed.
• Further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Patient consent statement
We are using entirely anonymized images from CT scans. These do not contain any identifying marks and are not accompanied by text that might identify the individual concerned.
Credit author statement
Jennifer Dennison: Writing-Original draft preparation and Editing, Investigation, Visualization: Samuel Carlson: Writing-Original draft preparation and Editing: Shannon Faehling: Writing-Original draft preparation and Editing: Hannah Phelan: Writing-Review and Editing: Muhammad Tariq: Writing-Review and Editing Ateeq Mubarik: Writing-Review and Editing, Supervision.
Institutional review board statement: Institutional Review Board approval was not necessary for our report.
Funding: None. The authors did not receive grant or outside funding in support of their research or preparation of this manuscript. They did not receive payment or any benefits from commercial entities.Declaration of competing interest
All authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33619439 | 19,173,777 | 2021-05 |
What was the dosage of drug 'ENOXAPARIN'? | Splenic infarction and spontaneous rectus sheath hematomas in COVID-19 patient.
Multiple studies and reports have suggested that coronavirus disease-19 (COVID-19) promotes arterial and venous thrombotic events in multiple organ systems, although the mechanism leading to a hypercoagulable state is still unknown. Few cases of splenic infarction associated with COVID-19 have been reported, of which half were found incidentally upon autopsy. This may be due to a clinically silent presentation or the symptoms being wrongfully attributed to pain caused by the effects of COVID-19. Due to the rarity of the condition and its lack of consistent symptomatology, splenic thromboembolism can be difficult to diagnose. Awareness of the condition and high clinical suspicion will help the clinician identify and manage the problem. Hemorrhage in patients with COVID-19 is uncommon in the hypercoagulable state that threatens thrombus formation in patients with COVID-19 infection. Despite prophylactic treatment with anticoagulation therapies, patients are more prone to developing clots. It is also well-known that therapeutic anticoagulation can place patients at a higher risk of bleeding. Thus, this unique population is at risk of developing both thrombotic and hemorrhagic events. We report a rare case of splenic infarction in a patient with confirmed COVID-19 infection despite prophylactic treatment with low-molecular-weight heparin which was found incidentally during workup for 2 other rare conditions: spontaneous rectus sheath hematoma and microhemorrhage or thrombus of the mesenteric vessels.
Introduction
In December 2019, the first cases of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported in Wuhan, China. Since, there have been 95,612,831 confirmed cases of COVID-19, including 2,066,176 deaths, reported to the World Health Organization [1]. Multiple studies have been done to examine clinical and epidemiologic aspects of the disease [2], [3], [4], [5], [6], [7]. It is well established that COVID-19 has a myriad of presentations, ranging from asymptomatic to severe illness; the most severe cases being observed in the elderly and those with comorbid conditions [8,9]. COVID-19 predominantly attacks the pulmonary system, and causes acute lung injury and diffuse alveolar damage, but it also has been shown to affect multiple systems in patients with and without comorbidities. Literature suggests that infection with COVID-19 provokes arterial and venous thrombotic events [10], and could be contributing to the multisystem damage. In an autopsy study done by Falasca et al histopathological hallmarks of widespread vascular injury were found in the liver, kidney, bone marrow, and spleen [3]. The exact mechanism causing these findings is not yet understood, but it is theorized to be a distinct process unique to the Sars-Cov-2 virus [10]. The current postulations attribute the pathophysiological mechanisms of COVID-19-related hypercoagulopathy to systemic inflammatory response syndrome (SIRS) precipitated by cytokine storm or activation of the coagulation cascade due to cellular activation triggered by the virus, or both [11]. These pathologies are quantified by measurement of the D-dimer and fibrin degradation product levels which have been shown to correlate with the severity of disease and patient prognosis [7].
Interestingly, the patient we present suffered one confirmed and one possible hemorrhagic event as a result of being anticoagulated to prevent further thrombus formation. 80 mg prophylactic LMWH was being administered twice daily, but the measured D-dimer remained markedly elevated. COVID-19-related hypercoagulopathy dictates that clinically-overt bleeding is uncommon in the setting of COVID-19 [12]. However, bleeding is a risk of therapeutic anticoagulation. Our patient spontaneously developed bilateral rectus sheath hematomas (RSH) as well as mesenteric vessel microhemorrhage. Rectus sheath hematoma is an uncommon cause of acute abdomen and can be benign, but in the setting of a patient receiving anticoagulation agents, can quickly progress to a life-threatening event. To date, there is only one other case reported of rectus sheath hematoma in a patient with COVID-19 [13]. Splenic infarct, mesenteric vessel infarct, and rectus sheath hematoma are rare in COVID-19 patients and providers should be aware of these potential complications. We present a case where all 3 are concurrently present in the same patient.
Narrative
A male in his 70s with a past medical history of hypertension, benign prostatic hypertrophy, gastroesophageal reflux disease, and depression presented to the emergency department with a chief complaint of worsening dyspnea. Seven days prior, the patient developed a dry cough with sore throat, and subsequently tested positive for COVID-19 which he had been managing at home on an outpatient basis. Since his COVID-19 diagnosis, his symptoms continued to worsen, and upon arrival to the emergency department he had dyspnea at rest, nonproductive cough, fevers, nausea, decreased appetite, and weakness. He was found to be in acute hypoxic respiratory failure with oxygen saturation (O2 SAT) of 68% on room air. His O2 SAT increased to 88%-92% on a 15% nonrebreather mask. He was also tachypneic at 22 breaths per minute and afebrile at 37.6 °C. Chest X-ray revealed new extensive patchy consolidative opacities about the lungs, favored to represent multifocal pneumonia. Laboratory evaluation was significant for elevated D-dimer, fibrinogen, and ferritin at 14.41 mg/L, 620 mg/dL and 1973 mg/mL, respectively. Additionally, lactic acid and white blood cell count were both elevated at 2.6 mmol/L and 14,900 cells/uL, respectively. Blood and urine cultures were negative. Treatment with enoxaparin, dexamethasone, and remdesivir was initiated as the patient was admitted to the intensive care unit for inpatient management of sepsis, viral pneumonia, severe COVID-19 infection, and acute hypoxic respiratory failure.
On hospital admission day 2, repeat D-dimer continued to be elevated at 5.56 ng/mL. A duplex ultrasound examination of the bilateral lower extremities was performed which revealed no evidence of intraluminal thrombus. Over the course of the next few days, the patient reported improved symptomatology and resolved dyspnea. His acute hypoxic respiratory failure was improving; he was reduced from 90% FiO2 on BiPAP to 45% FiO2, high-flow nasal cannula/BiPAP. His care was transferred from intensive care to intermediate care. His D-dimer continued to be elevated at 4.20, 3.78, and 4.58 ng/mL on hospital admission days 3, 4, and 5, respectively.
On the morning of hospital admission day 6, the patient continued to endorse improvement of symptoms, including no nausea, vomiting, fever, or chills, but he began to complain of constipation. To manage said constipation, the patient was given 30 mL oral lactulose for symptomatic relief.
Later that evening, the patient had a large bowel movement. Subsequently, the patient experienced acute onset of severe left lower quadrant abdominal pain. CT scan of the abdomen and pelvis with intravenous contrast revealed several findings. A 4 cm well-demarcated area of nonenhancement within the anterior superior spleen (Fig. 1) consistent with acute infarct was seen. Additionally, there was inflammation within fat surrounding the mesenteric vessels in the left upper quadrant (Fig. 2) which was suspected to be microhemorrhage or thrombosis. There were also large hematomas within the bilateral rectus muscles (Fig. 3, Fig. 4, Fig. 5) beginning just above the umbilicus extending down to the pubis measuring 5.6 cm × 18 cm on the left (Fig. 4) and 7 cm × 4 cm × 10 cm on the right (Figs. 4 and 5). Contrast within the hematomas suggested active bleeding at the time of imaging (Fig. 3). Hemoglobin was tested and was found to have decreased from 13.7 g/dL at the time of admission to 10.7 g/dL shortly after the time of CT scan. The patient's full dose enoxaparin, which was initially started due to significantly elevated D-dimer, was subsequently discontinued due to the presence of actively bleeding hematomas, despite the presence of a splenic infarct. When measured earlier that morning, his D-dimer continued to be elevated at 3.90 mg/mL.Fig. 1 Axial CT image of the abdomen demonstrating a 4 cm well-demarcated area of nonenhancement within the spleen on abdominal CT with IV contrast.
Fig 1
Fig. 2 Coronal abdominal CT image of the abdomen/pelvis demonstrating edema and fat stranding surrounding the left upper quadrant mesenteric vessels (red oval). This was thought to be due to mesenteric vessel microthrombi or hemorrhage. A definitive diagnosis was never established.
Fig. 2
Fig. 3 Axial CT image of the abdomen/pelvis demonstrating large hematomas within the bilateral rectus muscles (red arrows). Contrast within the left hematoma (red arrowhead) suggests active bleeding at the time of imaging. Dense fluid within the pelvis and along intrapelvic fascial planes is consistent with hemorrhage.
Fig. 3
Fig. 4 Sagittal CT images of the abdomen/pelvis with length measurement of the right and left rectus sheath hematomas.
Fig 4
Fig. 5 Axial CT image of the abdomen/pelvis with diameter measurements of the right rectus sheath hematoma.
Fig 5
At this time, the decision was made to transfer the patient by helicopter to a tertiary care center for possible interventional radiology embolization as well as management of the large rectus hematomas. At this point, the patient had received 6 doses of IV remdesevir out of 10 as well as 6 days of IV dexamethasone. The patient was stable at the time of transfer.
After 2 days of in-patient care at the tertiary center, it was determined that the active bleeding had stopped, and the hematomas remained stable. The patient's COVID-19 symptoms had also improved, and he was able to maintain adequate oxygenation levels while ambulating. The patient was discharged to complete his recovery at home. His recovery course has gone well without complications and as of 2 months following discharge he has been able to safely return to normal activity.
Discussion
COVID-19 infection is well known to cause hypercoagulability with pulmonary emboli being the most common presentation, splenic artery embolism and splenic infarction are rarely reported [14], [15], [16]. Splenic infarct is a rare cause of abdominal pain, often secondary to a hypercoagulable state [7]. COVID-19 hypercoagulability has been proposed to occur due to elevation of proinflammatory cytokines, including IL-6 [14], [15], [16]. Additionally, elevated D-dimer and fibrinogen degradation products are associated with poorer disease prognosis, potentially related to risk of disseminated intravascular coagulation [16]. Thus, treatment of the hypercoagulable state with antithrombotic agents is appropriate.
In a brief literature review, we identified 5 case studies consisting of 6 patients with involvement of splenic thromboembolism secondary to COVID-19 infection, including one case of atraumatic splenic rupture, and one case of hemoperitoneum [7,10,[17], [18], [19]. Additionally, multiple post-mortem autopsies have identified splenic involvement secondary to COVID-19 infection [2], [3], [4], [5], [6]. There have also been 2 cases of psoas hematoma [20,21]. As of yet, there has been only one prior report of rectus sheath hematoma secondary to COVID-19 coagulopathy [13].
Abdominal scans are not routinely performed in COVID-19 patients as primary symptomatology involves the respiratory tract. Thus, only symptomatic splenic infarctions or those found incidentally on CT scans of the chest extending into the abdomen may be identified. Evidence of splenic involvement has been noted on autopsy in patients known to have had COVID-19 [2], [3], [4], [5], [6]. This suggests that the presence of splenic involvement due to COVID-19 hypercoagulability may be higher than reported. While most cases of splenic infarct may be asymptomatic, atraumatic splenic rupture can be a devastating complication and necessitates a high clinical index of suspicion for patients with abdominal pain and concurrent or prior COVID-19 infection.
Rectus sheath hematoma is an uncommon complication of anticoagulation therapy. Other risk factors include old age, female gender, history of abdominal surgery/trauma/injections, cancer, coagulopathies, and renal impairment [22]. We hypothesize that the development of RSH in our patient was due to shearing of the epigastric vessels caused by the combination of anticoagulation therapy and trauma caused by straining and/or coughing. Early diagnosis and intervention are key to improving patient mortality and morbidity. CT scan with IV contrast is considered the gold standard [22], for identification of bleeding and for differentiating between arterial and venous bleeds [13] In cases where conservative management is unsuccessful, or the patient presents with severe clinical criteria, CT angiography can be utilized to identify active bleeding and help in staging for interventional radiology treatment [23]. In patients who have contraindication to contrast, Doppler ultrasound and red cell scintigraphy can be used. The required treatment should be dictated by the severity of the RSH and status of the patient. Conservative therapy including a binder, rest and analgesics may be adequate in the stable patient, whereas patients with hemodynamic instability may require resuscitation using IV fluids and blood products. In patients who have been anticoagulated, intravascular coil embolization or rarely surgery to ligate the epigastric vessels, may be required to achieve adequate hemostatic control.
Conclusion
Splenic infarction in COVID-19 infection is rarely reported and may go undetected if symptoms are vague or obscured by other ailments such as constipation, placing patients at risk of splenic rupture. Likewise, SRSH are also rare, a source for abdominal pain and a potentially serious condition especially in the anticoagulated patient, necessitating emergent treatment and the need to weigh the risks of hemorrhage versus thrombus when considering anticoagulation reversal. Despite their rarity, these conditions are treatable and should be considered in COVID-19 patients with abdominal pain and radiologists should monitor for thrombosis to aid in early diagnosis. Additionally, further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Learning points
• COVID-19 is well known to predispose patients for hypercoagulable events and complications, including thrombosis of unusual locations such as splenic artery branches.
• Anticoagulant management of acute thrombotic events in COVID-19 is critical in prevention of morbidity and mortality.
• Full anticoagulation predisposes patients to adverse effects related to bleeding and hemorrhage, including rectus sheath hematoma.
• There are no clear guidelines on management of hemorrhagic events in patients on therapeutic anticoagulation as treatment of ischemia due to thrombus, the risks of hemorrhage versus thrombosis must be weighed.
• Further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Patient consent statement
We are using entirely anonymized images from CT scans. These do not contain any identifying marks and are not accompanied by text that might identify the individual concerned.
Credit author statement
Jennifer Dennison: Writing-Original draft preparation and Editing, Investigation, Visualization: Samuel Carlson: Writing-Original draft preparation and Editing: Shannon Faehling: Writing-Original draft preparation and Editing: Hannah Phelan: Writing-Review and Editing: Muhammad Tariq: Writing-Review and Editing Ateeq Mubarik: Writing-Review and Editing, Supervision.
Institutional review board statement: Institutional Review Board approval was not necessary for our report.
Funding: None. The authors did not receive grant or outside funding in support of their research or preparation of this manuscript. They did not receive payment or any benefits from commercial entities.Declaration of competing interest
All authors declare that they have no competing interests. | 80 MILLIGRAM, BID | DrugDosageText | CC BY-NC-ND | 33619439 | 19,173,777 | 2021-05 |
What was the dosage of drug 'REMDESIVIR'? | Splenic infarction and spontaneous rectus sheath hematomas in COVID-19 patient.
Multiple studies and reports have suggested that coronavirus disease-19 (COVID-19) promotes arterial and venous thrombotic events in multiple organ systems, although the mechanism leading to a hypercoagulable state is still unknown. Few cases of splenic infarction associated with COVID-19 have been reported, of which half were found incidentally upon autopsy. This may be due to a clinically silent presentation or the symptoms being wrongfully attributed to pain caused by the effects of COVID-19. Due to the rarity of the condition and its lack of consistent symptomatology, splenic thromboembolism can be difficult to diagnose. Awareness of the condition and high clinical suspicion will help the clinician identify and manage the problem. Hemorrhage in patients with COVID-19 is uncommon in the hypercoagulable state that threatens thrombus formation in patients with COVID-19 infection. Despite prophylactic treatment with anticoagulation therapies, patients are more prone to developing clots. It is also well-known that therapeutic anticoagulation can place patients at a higher risk of bleeding. Thus, this unique population is at risk of developing both thrombotic and hemorrhagic events. We report a rare case of splenic infarction in a patient with confirmed COVID-19 infection despite prophylactic treatment with low-molecular-weight heparin which was found incidentally during workup for 2 other rare conditions: spontaneous rectus sheath hematoma and microhemorrhage or thrombus of the mesenteric vessels.
Introduction
In December 2019, the first cases of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported in Wuhan, China. Since, there have been 95,612,831 confirmed cases of COVID-19, including 2,066,176 deaths, reported to the World Health Organization [1]. Multiple studies have been done to examine clinical and epidemiologic aspects of the disease [2], [3], [4], [5], [6], [7]. It is well established that COVID-19 has a myriad of presentations, ranging from asymptomatic to severe illness; the most severe cases being observed in the elderly and those with comorbid conditions [8,9]. COVID-19 predominantly attacks the pulmonary system, and causes acute lung injury and diffuse alveolar damage, but it also has been shown to affect multiple systems in patients with and without comorbidities. Literature suggests that infection with COVID-19 provokes arterial and venous thrombotic events [10], and could be contributing to the multisystem damage. In an autopsy study done by Falasca et al histopathological hallmarks of widespread vascular injury were found in the liver, kidney, bone marrow, and spleen [3]. The exact mechanism causing these findings is not yet understood, but it is theorized to be a distinct process unique to the Sars-Cov-2 virus [10]. The current postulations attribute the pathophysiological mechanisms of COVID-19-related hypercoagulopathy to systemic inflammatory response syndrome (SIRS) precipitated by cytokine storm or activation of the coagulation cascade due to cellular activation triggered by the virus, or both [11]. These pathologies are quantified by measurement of the D-dimer and fibrin degradation product levels which have been shown to correlate with the severity of disease and patient prognosis [7].
Interestingly, the patient we present suffered one confirmed and one possible hemorrhagic event as a result of being anticoagulated to prevent further thrombus formation. 80 mg prophylactic LMWH was being administered twice daily, but the measured D-dimer remained markedly elevated. COVID-19-related hypercoagulopathy dictates that clinically-overt bleeding is uncommon in the setting of COVID-19 [12]. However, bleeding is a risk of therapeutic anticoagulation. Our patient spontaneously developed bilateral rectus sheath hematomas (RSH) as well as mesenteric vessel microhemorrhage. Rectus sheath hematoma is an uncommon cause of acute abdomen and can be benign, but in the setting of a patient receiving anticoagulation agents, can quickly progress to a life-threatening event. To date, there is only one other case reported of rectus sheath hematoma in a patient with COVID-19 [13]. Splenic infarct, mesenteric vessel infarct, and rectus sheath hematoma are rare in COVID-19 patients and providers should be aware of these potential complications. We present a case where all 3 are concurrently present in the same patient.
Narrative
A male in his 70s with a past medical history of hypertension, benign prostatic hypertrophy, gastroesophageal reflux disease, and depression presented to the emergency department with a chief complaint of worsening dyspnea. Seven days prior, the patient developed a dry cough with sore throat, and subsequently tested positive for COVID-19 which he had been managing at home on an outpatient basis. Since his COVID-19 diagnosis, his symptoms continued to worsen, and upon arrival to the emergency department he had dyspnea at rest, nonproductive cough, fevers, nausea, decreased appetite, and weakness. He was found to be in acute hypoxic respiratory failure with oxygen saturation (O2 SAT) of 68% on room air. His O2 SAT increased to 88%-92% on a 15% nonrebreather mask. He was also tachypneic at 22 breaths per minute and afebrile at 37.6 °C. Chest X-ray revealed new extensive patchy consolidative opacities about the lungs, favored to represent multifocal pneumonia. Laboratory evaluation was significant for elevated D-dimer, fibrinogen, and ferritin at 14.41 mg/L, 620 mg/dL and 1973 mg/mL, respectively. Additionally, lactic acid and white blood cell count were both elevated at 2.6 mmol/L and 14,900 cells/uL, respectively. Blood and urine cultures were negative. Treatment with enoxaparin, dexamethasone, and remdesivir was initiated as the patient was admitted to the intensive care unit for inpatient management of sepsis, viral pneumonia, severe COVID-19 infection, and acute hypoxic respiratory failure.
On hospital admission day 2, repeat D-dimer continued to be elevated at 5.56 ng/mL. A duplex ultrasound examination of the bilateral lower extremities was performed which revealed no evidence of intraluminal thrombus. Over the course of the next few days, the patient reported improved symptomatology and resolved dyspnea. His acute hypoxic respiratory failure was improving; he was reduced from 90% FiO2 on BiPAP to 45% FiO2, high-flow nasal cannula/BiPAP. His care was transferred from intensive care to intermediate care. His D-dimer continued to be elevated at 4.20, 3.78, and 4.58 ng/mL on hospital admission days 3, 4, and 5, respectively.
On the morning of hospital admission day 6, the patient continued to endorse improvement of symptoms, including no nausea, vomiting, fever, or chills, but he began to complain of constipation. To manage said constipation, the patient was given 30 mL oral lactulose for symptomatic relief.
Later that evening, the patient had a large bowel movement. Subsequently, the patient experienced acute onset of severe left lower quadrant abdominal pain. CT scan of the abdomen and pelvis with intravenous contrast revealed several findings. A 4 cm well-demarcated area of nonenhancement within the anterior superior spleen (Fig. 1) consistent with acute infarct was seen. Additionally, there was inflammation within fat surrounding the mesenteric vessels in the left upper quadrant (Fig. 2) which was suspected to be microhemorrhage or thrombosis. There were also large hematomas within the bilateral rectus muscles (Fig. 3, Fig. 4, Fig. 5) beginning just above the umbilicus extending down to the pubis measuring 5.6 cm × 18 cm on the left (Fig. 4) and 7 cm × 4 cm × 10 cm on the right (Figs. 4 and 5). Contrast within the hematomas suggested active bleeding at the time of imaging (Fig. 3). Hemoglobin was tested and was found to have decreased from 13.7 g/dL at the time of admission to 10.7 g/dL shortly after the time of CT scan. The patient's full dose enoxaparin, which was initially started due to significantly elevated D-dimer, was subsequently discontinued due to the presence of actively bleeding hematomas, despite the presence of a splenic infarct. When measured earlier that morning, his D-dimer continued to be elevated at 3.90 mg/mL.Fig. 1 Axial CT image of the abdomen demonstrating a 4 cm well-demarcated area of nonenhancement within the spleen on abdominal CT with IV contrast.
Fig 1
Fig. 2 Coronal abdominal CT image of the abdomen/pelvis demonstrating edema and fat stranding surrounding the left upper quadrant mesenteric vessels (red oval). This was thought to be due to mesenteric vessel microthrombi or hemorrhage. A definitive diagnosis was never established.
Fig. 2
Fig. 3 Axial CT image of the abdomen/pelvis demonstrating large hematomas within the bilateral rectus muscles (red arrows). Contrast within the left hematoma (red arrowhead) suggests active bleeding at the time of imaging. Dense fluid within the pelvis and along intrapelvic fascial planes is consistent with hemorrhage.
Fig. 3
Fig. 4 Sagittal CT images of the abdomen/pelvis with length measurement of the right and left rectus sheath hematomas.
Fig 4
Fig. 5 Axial CT image of the abdomen/pelvis with diameter measurements of the right rectus sheath hematoma.
Fig 5
At this time, the decision was made to transfer the patient by helicopter to a tertiary care center for possible interventional radiology embolization as well as management of the large rectus hematomas. At this point, the patient had received 6 doses of IV remdesevir out of 10 as well as 6 days of IV dexamethasone. The patient was stable at the time of transfer.
After 2 days of in-patient care at the tertiary center, it was determined that the active bleeding had stopped, and the hematomas remained stable. The patient's COVID-19 symptoms had also improved, and he was able to maintain adequate oxygenation levels while ambulating. The patient was discharged to complete his recovery at home. His recovery course has gone well without complications and as of 2 months following discharge he has been able to safely return to normal activity.
Discussion
COVID-19 infection is well known to cause hypercoagulability with pulmonary emboli being the most common presentation, splenic artery embolism and splenic infarction are rarely reported [14], [15], [16]. Splenic infarct is a rare cause of abdominal pain, often secondary to a hypercoagulable state [7]. COVID-19 hypercoagulability has been proposed to occur due to elevation of proinflammatory cytokines, including IL-6 [14], [15], [16]. Additionally, elevated D-dimer and fibrinogen degradation products are associated with poorer disease prognosis, potentially related to risk of disseminated intravascular coagulation [16]. Thus, treatment of the hypercoagulable state with antithrombotic agents is appropriate.
In a brief literature review, we identified 5 case studies consisting of 6 patients with involvement of splenic thromboembolism secondary to COVID-19 infection, including one case of atraumatic splenic rupture, and one case of hemoperitoneum [7,10,[17], [18], [19]. Additionally, multiple post-mortem autopsies have identified splenic involvement secondary to COVID-19 infection [2], [3], [4], [5], [6]. There have also been 2 cases of psoas hematoma [20,21]. As of yet, there has been only one prior report of rectus sheath hematoma secondary to COVID-19 coagulopathy [13].
Abdominal scans are not routinely performed in COVID-19 patients as primary symptomatology involves the respiratory tract. Thus, only symptomatic splenic infarctions or those found incidentally on CT scans of the chest extending into the abdomen may be identified. Evidence of splenic involvement has been noted on autopsy in patients known to have had COVID-19 [2], [3], [4], [5], [6]. This suggests that the presence of splenic involvement due to COVID-19 hypercoagulability may be higher than reported. While most cases of splenic infarct may be asymptomatic, atraumatic splenic rupture can be a devastating complication and necessitates a high clinical index of suspicion for patients with abdominal pain and concurrent or prior COVID-19 infection.
Rectus sheath hematoma is an uncommon complication of anticoagulation therapy. Other risk factors include old age, female gender, history of abdominal surgery/trauma/injections, cancer, coagulopathies, and renal impairment [22]. We hypothesize that the development of RSH in our patient was due to shearing of the epigastric vessels caused by the combination of anticoagulation therapy and trauma caused by straining and/or coughing. Early diagnosis and intervention are key to improving patient mortality and morbidity. CT scan with IV contrast is considered the gold standard [22], for identification of bleeding and for differentiating between arterial and venous bleeds [13] In cases where conservative management is unsuccessful, or the patient presents with severe clinical criteria, CT angiography can be utilized to identify active bleeding and help in staging for interventional radiology treatment [23]. In patients who have contraindication to contrast, Doppler ultrasound and red cell scintigraphy can be used. The required treatment should be dictated by the severity of the RSH and status of the patient. Conservative therapy including a binder, rest and analgesics may be adequate in the stable patient, whereas patients with hemodynamic instability may require resuscitation using IV fluids and blood products. In patients who have been anticoagulated, intravascular coil embolization or rarely surgery to ligate the epigastric vessels, may be required to achieve adequate hemostatic control.
Conclusion
Splenic infarction in COVID-19 infection is rarely reported and may go undetected if symptoms are vague or obscured by other ailments such as constipation, placing patients at risk of splenic rupture. Likewise, SRSH are also rare, a source for abdominal pain and a potentially serious condition especially in the anticoagulated patient, necessitating emergent treatment and the need to weigh the risks of hemorrhage versus thrombus when considering anticoagulation reversal. Despite their rarity, these conditions are treatable and should be considered in COVID-19 patients with abdominal pain and radiologists should monitor for thrombosis to aid in early diagnosis. Additionally, further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Learning points
• COVID-19 is well known to predispose patients for hypercoagulable events and complications, including thrombosis of unusual locations such as splenic artery branches.
• Anticoagulant management of acute thrombotic events in COVID-19 is critical in prevention of morbidity and mortality.
• Full anticoagulation predisposes patients to adverse effects related to bleeding and hemorrhage, including rectus sheath hematoma.
• There are no clear guidelines on management of hemorrhagic events in patients on therapeutic anticoagulation as treatment of ischemia due to thrombus, the risks of hemorrhage versus thrombosis must be weighed.
• Further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Patient consent statement
We are using entirely anonymized images from CT scans. These do not contain any identifying marks and are not accompanied by text that might identify the individual concerned.
Credit author statement
Jennifer Dennison: Writing-Original draft preparation and Editing, Investigation, Visualization: Samuel Carlson: Writing-Original draft preparation and Editing: Shannon Faehling: Writing-Original draft preparation and Editing: Hannah Phelan: Writing-Review and Editing: Muhammad Tariq: Writing-Review and Editing Ateeq Mubarik: Writing-Review and Editing, Supervision.
Institutional review board statement: Institutional Review Board approval was not necessary for our report.
Funding: None. The authors did not receive grant or outside funding in support of their research or preparation of this manuscript. They did not receive payment or any benefits from commercial entities.Declaration of competing interest
All authors declare that they have no competing interests. | 6 DOSAGE FORM | DrugDosageText | CC BY-NC-ND | 33619439 | 19,173,777 | 2021-05 |
What was the outcome of reaction 'Abdominal wall haematoma'? | Splenic infarction and spontaneous rectus sheath hematomas in COVID-19 patient.
Multiple studies and reports have suggested that coronavirus disease-19 (COVID-19) promotes arterial and venous thrombotic events in multiple organ systems, although the mechanism leading to a hypercoagulable state is still unknown. Few cases of splenic infarction associated with COVID-19 have been reported, of which half were found incidentally upon autopsy. This may be due to a clinically silent presentation or the symptoms being wrongfully attributed to pain caused by the effects of COVID-19. Due to the rarity of the condition and its lack of consistent symptomatology, splenic thromboembolism can be difficult to diagnose. Awareness of the condition and high clinical suspicion will help the clinician identify and manage the problem. Hemorrhage in patients with COVID-19 is uncommon in the hypercoagulable state that threatens thrombus formation in patients with COVID-19 infection. Despite prophylactic treatment with anticoagulation therapies, patients are more prone to developing clots. It is also well-known that therapeutic anticoagulation can place patients at a higher risk of bleeding. Thus, this unique population is at risk of developing both thrombotic and hemorrhagic events. We report a rare case of splenic infarction in a patient with confirmed COVID-19 infection despite prophylactic treatment with low-molecular-weight heparin which was found incidentally during workup for 2 other rare conditions: spontaneous rectus sheath hematoma and microhemorrhage or thrombus of the mesenteric vessels.
Introduction
In December 2019, the first cases of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported in Wuhan, China. Since, there have been 95,612,831 confirmed cases of COVID-19, including 2,066,176 deaths, reported to the World Health Organization [1]. Multiple studies have been done to examine clinical and epidemiologic aspects of the disease [2], [3], [4], [5], [6], [7]. It is well established that COVID-19 has a myriad of presentations, ranging from asymptomatic to severe illness; the most severe cases being observed in the elderly and those with comorbid conditions [8,9]. COVID-19 predominantly attacks the pulmonary system, and causes acute lung injury and diffuse alveolar damage, but it also has been shown to affect multiple systems in patients with and without comorbidities. Literature suggests that infection with COVID-19 provokes arterial and venous thrombotic events [10], and could be contributing to the multisystem damage. In an autopsy study done by Falasca et al histopathological hallmarks of widespread vascular injury were found in the liver, kidney, bone marrow, and spleen [3]. The exact mechanism causing these findings is not yet understood, but it is theorized to be a distinct process unique to the Sars-Cov-2 virus [10]. The current postulations attribute the pathophysiological mechanisms of COVID-19-related hypercoagulopathy to systemic inflammatory response syndrome (SIRS) precipitated by cytokine storm or activation of the coagulation cascade due to cellular activation triggered by the virus, or both [11]. These pathologies are quantified by measurement of the D-dimer and fibrin degradation product levels which have been shown to correlate with the severity of disease and patient prognosis [7].
Interestingly, the patient we present suffered one confirmed and one possible hemorrhagic event as a result of being anticoagulated to prevent further thrombus formation. 80 mg prophylactic LMWH was being administered twice daily, but the measured D-dimer remained markedly elevated. COVID-19-related hypercoagulopathy dictates that clinically-overt bleeding is uncommon in the setting of COVID-19 [12]. However, bleeding is a risk of therapeutic anticoagulation. Our patient spontaneously developed bilateral rectus sheath hematomas (RSH) as well as mesenteric vessel microhemorrhage. Rectus sheath hematoma is an uncommon cause of acute abdomen and can be benign, but in the setting of a patient receiving anticoagulation agents, can quickly progress to a life-threatening event. To date, there is only one other case reported of rectus sheath hematoma in a patient with COVID-19 [13]. Splenic infarct, mesenteric vessel infarct, and rectus sheath hematoma are rare in COVID-19 patients and providers should be aware of these potential complications. We present a case where all 3 are concurrently present in the same patient.
Narrative
A male in his 70s with a past medical history of hypertension, benign prostatic hypertrophy, gastroesophageal reflux disease, and depression presented to the emergency department with a chief complaint of worsening dyspnea. Seven days prior, the patient developed a dry cough with sore throat, and subsequently tested positive for COVID-19 which he had been managing at home on an outpatient basis. Since his COVID-19 diagnosis, his symptoms continued to worsen, and upon arrival to the emergency department he had dyspnea at rest, nonproductive cough, fevers, nausea, decreased appetite, and weakness. He was found to be in acute hypoxic respiratory failure with oxygen saturation (O2 SAT) of 68% on room air. His O2 SAT increased to 88%-92% on a 15% nonrebreather mask. He was also tachypneic at 22 breaths per minute and afebrile at 37.6 °C. Chest X-ray revealed new extensive patchy consolidative opacities about the lungs, favored to represent multifocal pneumonia. Laboratory evaluation was significant for elevated D-dimer, fibrinogen, and ferritin at 14.41 mg/L, 620 mg/dL and 1973 mg/mL, respectively. Additionally, lactic acid and white blood cell count were both elevated at 2.6 mmol/L and 14,900 cells/uL, respectively. Blood and urine cultures were negative. Treatment with enoxaparin, dexamethasone, and remdesivir was initiated as the patient was admitted to the intensive care unit for inpatient management of sepsis, viral pneumonia, severe COVID-19 infection, and acute hypoxic respiratory failure.
On hospital admission day 2, repeat D-dimer continued to be elevated at 5.56 ng/mL. A duplex ultrasound examination of the bilateral lower extremities was performed which revealed no evidence of intraluminal thrombus. Over the course of the next few days, the patient reported improved symptomatology and resolved dyspnea. His acute hypoxic respiratory failure was improving; he was reduced from 90% FiO2 on BiPAP to 45% FiO2, high-flow nasal cannula/BiPAP. His care was transferred from intensive care to intermediate care. His D-dimer continued to be elevated at 4.20, 3.78, and 4.58 ng/mL on hospital admission days 3, 4, and 5, respectively.
On the morning of hospital admission day 6, the patient continued to endorse improvement of symptoms, including no nausea, vomiting, fever, or chills, but he began to complain of constipation. To manage said constipation, the patient was given 30 mL oral lactulose for symptomatic relief.
Later that evening, the patient had a large bowel movement. Subsequently, the patient experienced acute onset of severe left lower quadrant abdominal pain. CT scan of the abdomen and pelvis with intravenous contrast revealed several findings. A 4 cm well-demarcated area of nonenhancement within the anterior superior spleen (Fig. 1) consistent with acute infarct was seen. Additionally, there was inflammation within fat surrounding the mesenteric vessels in the left upper quadrant (Fig. 2) which was suspected to be microhemorrhage or thrombosis. There were also large hematomas within the bilateral rectus muscles (Fig. 3, Fig. 4, Fig. 5) beginning just above the umbilicus extending down to the pubis measuring 5.6 cm × 18 cm on the left (Fig. 4) and 7 cm × 4 cm × 10 cm on the right (Figs. 4 and 5). Contrast within the hematomas suggested active bleeding at the time of imaging (Fig. 3). Hemoglobin was tested and was found to have decreased from 13.7 g/dL at the time of admission to 10.7 g/dL shortly after the time of CT scan. The patient's full dose enoxaparin, which was initially started due to significantly elevated D-dimer, was subsequently discontinued due to the presence of actively bleeding hematomas, despite the presence of a splenic infarct. When measured earlier that morning, his D-dimer continued to be elevated at 3.90 mg/mL.Fig. 1 Axial CT image of the abdomen demonstrating a 4 cm well-demarcated area of nonenhancement within the spleen on abdominal CT with IV contrast.
Fig 1
Fig. 2 Coronal abdominal CT image of the abdomen/pelvis demonstrating edema and fat stranding surrounding the left upper quadrant mesenteric vessels (red oval). This was thought to be due to mesenteric vessel microthrombi or hemorrhage. A definitive diagnosis was never established.
Fig. 2
Fig. 3 Axial CT image of the abdomen/pelvis demonstrating large hematomas within the bilateral rectus muscles (red arrows). Contrast within the left hematoma (red arrowhead) suggests active bleeding at the time of imaging. Dense fluid within the pelvis and along intrapelvic fascial planes is consistent with hemorrhage.
Fig. 3
Fig. 4 Sagittal CT images of the abdomen/pelvis with length measurement of the right and left rectus sheath hematomas.
Fig 4
Fig. 5 Axial CT image of the abdomen/pelvis with diameter measurements of the right rectus sheath hematoma.
Fig 5
At this time, the decision was made to transfer the patient by helicopter to a tertiary care center for possible interventional radiology embolization as well as management of the large rectus hematomas. At this point, the patient had received 6 doses of IV remdesevir out of 10 as well as 6 days of IV dexamethasone. The patient was stable at the time of transfer.
After 2 days of in-patient care at the tertiary center, it was determined that the active bleeding had stopped, and the hematomas remained stable. The patient's COVID-19 symptoms had also improved, and he was able to maintain adequate oxygenation levels while ambulating. The patient was discharged to complete his recovery at home. His recovery course has gone well without complications and as of 2 months following discharge he has been able to safely return to normal activity.
Discussion
COVID-19 infection is well known to cause hypercoagulability with pulmonary emboli being the most common presentation, splenic artery embolism and splenic infarction are rarely reported [14], [15], [16]. Splenic infarct is a rare cause of abdominal pain, often secondary to a hypercoagulable state [7]. COVID-19 hypercoagulability has been proposed to occur due to elevation of proinflammatory cytokines, including IL-6 [14], [15], [16]. Additionally, elevated D-dimer and fibrinogen degradation products are associated with poorer disease prognosis, potentially related to risk of disseminated intravascular coagulation [16]. Thus, treatment of the hypercoagulable state with antithrombotic agents is appropriate.
In a brief literature review, we identified 5 case studies consisting of 6 patients with involvement of splenic thromboembolism secondary to COVID-19 infection, including one case of atraumatic splenic rupture, and one case of hemoperitoneum [7,10,[17], [18], [19]. Additionally, multiple post-mortem autopsies have identified splenic involvement secondary to COVID-19 infection [2], [3], [4], [5], [6]. There have also been 2 cases of psoas hematoma [20,21]. As of yet, there has been only one prior report of rectus sheath hematoma secondary to COVID-19 coagulopathy [13].
Abdominal scans are not routinely performed in COVID-19 patients as primary symptomatology involves the respiratory tract. Thus, only symptomatic splenic infarctions or those found incidentally on CT scans of the chest extending into the abdomen may be identified. Evidence of splenic involvement has been noted on autopsy in patients known to have had COVID-19 [2], [3], [4], [5], [6]. This suggests that the presence of splenic involvement due to COVID-19 hypercoagulability may be higher than reported. While most cases of splenic infarct may be asymptomatic, atraumatic splenic rupture can be a devastating complication and necessitates a high clinical index of suspicion for patients with abdominal pain and concurrent or prior COVID-19 infection.
Rectus sheath hematoma is an uncommon complication of anticoagulation therapy. Other risk factors include old age, female gender, history of abdominal surgery/trauma/injections, cancer, coagulopathies, and renal impairment [22]. We hypothesize that the development of RSH in our patient was due to shearing of the epigastric vessels caused by the combination of anticoagulation therapy and trauma caused by straining and/or coughing. Early diagnosis and intervention are key to improving patient mortality and morbidity. CT scan with IV contrast is considered the gold standard [22], for identification of bleeding and for differentiating between arterial and venous bleeds [13] In cases where conservative management is unsuccessful, or the patient presents with severe clinical criteria, CT angiography can be utilized to identify active bleeding and help in staging for interventional radiology treatment [23]. In patients who have contraindication to contrast, Doppler ultrasound and red cell scintigraphy can be used. The required treatment should be dictated by the severity of the RSH and status of the patient. Conservative therapy including a binder, rest and analgesics may be adequate in the stable patient, whereas patients with hemodynamic instability may require resuscitation using IV fluids and blood products. In patients who have been anticoagulated, intravascular coil embolization or rarely surgery to ligate the epigastric vessels, may be required to achieve adequate hemostatic control.
Conclusion
Splenic infarction in COVID-19 infection is rarely reported and may go undetected if symptoms are vague or obscured by other ailments such as constipation, placing patients at risk of splenic rupture. Likewise, SRSH are also rare, a source for abdominal pain and a potentially serious condition especially in the anticoagulated patient, necessitating emergent treatment and the need to weigh the risks of hemorrhage versus thrombus when considering anticoagulation reversal. Despite their rarity, these conditions are treatable and should be considered in COVID-19 patients with abdominal pain and radiologists should monitor for thrombosis to aid in early diagnosis. Additionally, further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Learning points
• COVID-19 is well known to predispose patients for hypercoagulable events and complications, including thrombosis of unusual locations such as splenic artery branches.
• Anticoagulant management of acute thrombotic events in COVID-19 is critical in prevention of morbidity and mortality.
• Full anticoagulation predisposes patients to adverse effects related to bleeding and hemorrhage, including rectus sheath hematoma.
• There are no clear guidelines on management of hemorrhagic events in patients on therapeutic anticoagulation as treatment of ischemia due to thrombus, the risks of hemorrhage versus thrombosis must be weighed.
• Further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Patient consent statement
We are using entirely anonymized images from CT scans. These do not contain any identifying marks and are not accompanied by text that might identify the individual concerned.
Credit author statement
Jennifer Dennison: Writing-Original draft preparation and Editing, Investigation, Visualization: Samuel Carlson: Writing-Original draft preparation and Editing: Shannon Faehling: Writing-Original draft preparation and Editing: Hannah Phelan: Writing-Review and Editing: Muhammad Tariq: Writing-Review and Editing Ateeq Mubarik: Writing-Review and Editing, Supervision.
Institutional review board statement: Institutional Review Board approval was not necessary for our report.
Funding: None. The authors did not receive grant or outside funding in support of their research or preparation of this manuscript. They did not receive payment or any benefits from commercial entities.Declaration of competing interest
All authors declare that they have no competing interests. | Not recovered | ReactionOutcome | CC BY-NC-ND | 33619439 | 19,173,777 | 2021-05 |
What was the outcome of reaction 'Haemorrhage'? | Splenic infarction and spontaneous rectus sheath hematomas in COVID-19 patient.
Multiple studies and reports have suggested that coronavirus disease-19 (COVID-19) promotes arterial and venous thrombotic events in multiple organ systems, although the mechanism leading to a hypercoagulable state is still unknown. Few cases of splenic infarction associated with COVID-19 have been reported, of which half were found incidentally upon autopsy. This may be due to a clinically silent presentation or the symptoms being wrongfully attributed to pain caused by the effects of COVID-19. Due to the rarity of the condition and its lack of consistent symptomatology, splenic thromboembolism can be difficult to diagnose. Awareness of the condition and high clinical suspicion will help the clinician identify and manage the problem. Hemorrhage in patients with COVID-19 is uncommon in the hypercoagulable state that threatens thrombus formation in patients with COVID-19 infection. Despite prophylactic treatment with anticoagulation therapies, patients are more prone to developing clots. It is also well-known that therapeutic anticoagulation can place patients at a higher risk of bleeding. Thus, this unique population is at risk of developing both thrombotic and hemorrhagic events. We report a rare case of splenic infarction in a patient with confirmed COVID-19 infection despite prophylactic treatment with low-molecular-weight heparin which was found incidentally during workup for 2 other rare conditions: spontaneous rectus sheath hematoma and microhemorrhage or thrombus of the mesenteric vessels.
Introduction
In December 2019, the first cases of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were reported in Wuhan, China. Since, there have been 95,612,831 confirmed cases of COVID-19, including 2,066,176 deaths, reported to the World Health Organization [1]. Multiple studies have been done to examine clinical and epidemiologic aspects of the disease [2], [3], [4], [5], [6], [7]. It is well established that COVID-19 has a myriad of presentations, ranging from asymptomatic to severe illness; the most severe cases being observed in the elderly and those with comorbid conditions [8,9]. COVID-19 predominantly attacks the pulmonary system, and causes acute lung injury and diffuse alveolar damage, but it also has been shown to affect multiple systems in patients with and without comorbidities. Literature suggests that infection with COVID-19 provokes arterial and venous thrombotic events [10], and could be contributing to the multisystem damage. In an autopsy study done by Falasca et al histopathological hallmarks of widespread vascular injury were found in the liver, kidney, bone marrow, and spleen [3]. The exact mechanism causing these findings is not yet understood, but it is theorized to be a distinct process unique to the Sars-Cov-2 virus [10]. The current postulations attribute the pathophysiological mechanisms of COVID-19-related hypercoagulopathy to systemic inflammatory response syndrome (SIRS) precipitated by cytokine storm or activation of the coagulation cascade due to cellular activation triggered by the virus, or both [11]. These pathologies are quantified by measurement of the D-dimer and fibrin degradation product levels which have been shown to correlate with the severity of disease and patient prognosis [7].
Interestingly, the patient we present suffered one confirmed and one possible hemorrhagic event as a result of being anticoagulated to prevent further thrombus formation. 80 mg prophylactic LMWH was being administered twice daily, but the measured D-dimer remained markedly elevated. COVID-19-related hypercoagulopathy dictates that clinically-overt bleeding is uncommon in the setting of COVID-19 [12]. However, bleeding is a risk of therapeutic anticoagulation. Our patient spontaneously developed bilateral rectus sheath hematomas (RSH) as well as mesenteric vessel microhemorrhage. Rectus sheath hematoma is an uncommon cause of acute abdomen and can be benign, but in the setting of a patient receiving anticoagulation agents, can quickly progress to a life-threatening event. To date, there is only one other case reported of rectus sheath hematoma in a patient with COVID-19 [13]. Splenic infarct, mesenteric vessel infarct, and rectus sheath hematoma are rare in COVID-19 patients and providers should be aware of these potential complications. We present a case where all 3 are concurrently present in the same patient.
Narrative
A male in his 70s with a past medical history of hypertension, benign prostatic hypertrophy, gastroesophageal reflux disease, and depression presented to the emergency department with a chief complaint of worsening dyspnea. Seven days prior, the patient developed a dry cough with sore throat, and subsequently tested positive for COVID-19 which he had been managing at home on an outpatient basis. Since his COVID-19 diagnosis, his symptoms continued to worsen, and upon arrival to the emergency department he had dyspnea at rest, nonproductive cough, fevers, nausea, decreased appetite, and weakness. He was found to be in acute hypoxic respiratory failure with oxygen saturation (O2 SAT) of 68% on room air. His O2 SAT increased to 88%-92% on a 15% nonrebreather mask. He was also tachypneic at 22 breaths per minute and afebrile at 37.6 °C. Chest X-ray revealed new extensive patchy consolidative opacities about the lungs, favored to represent multifocal pneumonia. Laboratory evaluation was significant for elevated D-dimer, fibrinogen, and ferritin at 14.41 mg/L, 620 mg/dL and 1973 mg/mL, respectively. Additionally, lactic acid and white blood cell count were both elevated at 2.6 mmol/L and 14,900 cells/uL, respectively. Blood and urine cultures were negative. Treatment with enoxaparin, dexamethasone, and remdesivir was initiated as the patient was admitted to the intensive care unit for inpatient management of sepsis, viral pneumonia, severe COVID-19 infection, and acute hypoxic respiratory failure.
On hospital admission day 2, repeat D-dimer continued to be elevated at 5.56 ng/mL. A duplex ultrasound examination of the bilateral lower extremities was performed which revealed no evidence of intraluminal thrombus. Over the course of the next few days, the patient reported improved symptomatology and resolved dyspnea. His acute hypoxic respiratory failure was improving; he was reduced from 90% FiO2 on BiPAP to 45% FiO2, high-flow nasal cannula/BiPAP. His care was transferred from intensive care to intermediate care. His D-dimer continued to be elevated at 4.20, 3.78, and 4.58 ng/mL on hospital admission days 3, 4, and 5, respectively.
On the morning of hospital admission day 6, the patient continued to endorse improvement of symptoms, including no nausea, vomiting, fever, or chills, but he began to complain of constipation. To manage said constipation, the patient was given 30 mL oral lactulose for symptomatic relief.
Later that evening, the patient had a large bowel movement. Subsequently, the patient experienced acute onset of severe left lower quadrant abdominal pain. CT scan of the abdomen and pelvis with intravenous contrast revealed several findings. A 4 cm well-demarcated area of nonenhancement within the anterior superior spleen (Fig. 1) consistent with acute infarct was seen. Additionally, there was inflammation within fat surrounding the mesenteric vessels in the left upper quadrant (Fig. 2) which was suspected to be microhemorrhage or thrombosis. There were also large hematomas within the bilateral rectus muscles (Fig. 3, Fig. 4, Fig. 5) beginning just above the umbilicus extending down to the pubis measuring 5.6 cm × 18 cm on the left (Fig. 4) and 7 cm × 4 cm × 10 cm on the right (Figs. 4 and 5). Contrast within the hematomas suggested active bleeding at the time of imaging (Fig. 3). Hemoglobin was tested and was found to have decreased from 13.7 g/dL at the time of admission to 10.7 g/dL shortly after the time of CT scan. The patient's full dose enoxaparin, which was initially started due to significantly elevated D-dimer, was subsequently discontinued due to the presence of actively bleeding hematomas, despite the presence of a splenic infarct. When measured earlier that morning, his D-dimer continued to be elevated at 3.90 mg/mL.Fig. 1 Axial CT image of the abdomen demonstrating a 4 cm well-demarcated area of nonenhancement within the spleen on abdominal CT with IV contrast.
Fig 1
Fig. 2 Coronal abdominal CT image of the abdomen/pelvis demonstrating edema and fat stranding surrounding the left upper quadrant mesenteric vessels (red oval). This was thought to be due to mesenteric vessel microthrombi or hemorrhage. A definitive diagnosis was never established.
Fig. 2
Fig. 3 Axial CT image of the abdomen/pelvis demonstrating large hematomas within the bilateral rectus muscles (red arrows). Contrast within the left hematoma (red arrowhead) suggests active bleeding at the time of imaging. Dense fluid within the pelvis and along intrapelvic fascial planes is consistent with hemorrhage.
Fig. 3
Fig. 4 Sagittal CT images of the abdomen/pelvis with length measurement of the right and left rectus sheath hematomas.
Fig 4
Fig. 5 Axial CT image of the abdomen/pelvis with diameter measurements of the right rectus sheath hematoma.
Fig 5
At this time, the decision was made to transfer the patient by helicopter to a tertiary care center for possible interventional radiology embolization as well as management of the large rectus hematomas. At this point, the patient had received 6 doses of IV remdesevir out of 10 as well as 6 days of IV dexamethasone. The patient was stable at the time of transfer.
After 2 days of in-patient care at the tertiary center, it was determined that the active bleeding had stopped, and the hematomas remained stable. The patient's COVID-19 symptoms had also improved, and he was able to maintain adequate oxygenation levels while ambulating. The patient was discharged to complete his recovery at home. His recovery course has gone well without complications and as of 2 months following discharge he has been able to safely return to normal activity.
Discussion
COVID-19 infection is well known to cause hypercoagulability with pulmonary emboli being the most common presentation, splenic artery embolism and splenic infarction are rarely reported [14], [15], [16]. Splenic infarct is a rare cause of abdominal pain, often secondary to a hypercoagulable state [7]. COVID-19 hypercoagulability has been proposed to occur due to elevation of proinflammatory cytokines, including IL-6 [14], [15], [16]. Additionally, elevated D-dimer and fibrinogen degradation products are associated with poorer disease prognosis, potentially related to risk of disseminated intravascular coagulation [16]. Thus, treatment of the hypercoagulable state with antithrombotic agents is appropriate.
In a brief literature review, we identified 5 case studies consisting of 6 patients with involvement of splenic thromboembolism secondary to COVID-19 infection, including one case of atraumatic splenic rupture, and one case of hemoperitoneum [7,10,[17], [18], [19]. Additionally, multiple post-mortem autopsies have identified splenic involvement secondary to COVID-19 infection [2], [3], [4], [5], [6]. There have also been 2 cases of psoas hematoma [20,21]. As of yet, there has been only one prior report of rectus sheath hematoma secondary to COVID-19 coagulopathy [13].
Abdominal scans are not routinely performed in COVID-19 patients as primary symptomatology involves the respiratory tract. Thus, only symptomatic splenic infarctions or those found incidentally on CT scans of the chest extending into the abdomen may be identified. Evidence of splenic involvement has been noted on autopsy in patients known to have had COVID-19 [2], [3], [4], [5], [6]. This suggests that the presence of splenic involvement due to COVID-19 hypercoagulability may be higher than reported. While most cases of splenic infarct may be asymptomatic, atraumatic splenic rupture can be a devastating complication and necessitates a high clinical index of suspicion for patients with abdominal pain and concurrent or prior COVID-19 infection.
Rectus sheath hematoma is an uncommon complication of anticoagulation therapy. Other risk factors include old age, female gender, history of abdominal surgery/trauma/injections, cancer, coagulopathies, and renal impairment [22]. We hypothesize that the development of RSH in our patient was due to shearing of the epigastric vessels caused by the combination of anticoagulation therapy and trauma caused by straining and/or coughing. Early diagnosis and intervention are key to improving patient mortality and morbidity. CT scan with IV contrast is considered the gold standard [22], for identification of bleeding and for differentiating between arterial and venous bleeds [13] In cases where conservative management is unsuccessful, or the patient presents with severe clinical criteria, CT angiography can be utilized to identify active bleeding and help in staging for interventional radiology treatment [23]. In patients who have contraindication to contrast, Doppler ultrasound and red cell scintigraphy can be used. The required treatment should be dictated by the severity of the RSH and status of the patient. Conservative therapy including a binder, rest and analgesics may be adequate in the stable patient, whereas patients with hemodynamic instability may require resuscitation using IV fluids and blood products. In patients who have been anticoagulated, intravascular coil embolization or rarely surgery to ligate the epigastric vessels, may be required to achieve adequate hemostatic control.
Conclusion
Splenic infarction in COVID-19 infection is rarely reported and may go undetected if symptoms are vague or obscured by other ailments such as constipation, placing patients at risk of splenic rupture. Likewise, SRSH are also rare, a source for abdominal pain and a potentially serious condition especially in the anticoagulated patient, necessitating emergent treatment and the need to weigh the risks of hemorrhage versus thrombus when considering anticoagulation reversal. Despite their rarity, these conditions are treatable and should be considered in COVID-19 patients with abdominal pain and radiologists should monitor for thrombosis to aid in early diagnosis. Additionally, further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Learning points
• COVID-19 is well known to predispose patients for hypercoagulable events and complications, including thrombosis of unusual locations such as splenic artery branches.
• Anticoagulant management of acute thrombotic events in COVID-19 is critical in prevention of morbidity and mortality.
• Full anticoagulation predisposes patients to adverse effects related to bleeding and hemorrhage, including rectus sheath hematoma.
• There are no clear guidelines on management of hemorrhagic events in patients on therapeutic anticoagulation as treatment of ischemia due to thrombus, the risks of hemorrhage versus thrombosis must be weighed.
• Further research or reports on acute hemorrhage in COVID-19 patients receiving anticoagulation is recommended.
Patient consent statement
We are using entirely anonymized images from CT scans. These do not contain any identifying marks and are not accompanied by text that might identify the individual concerned.
Credit author statement
Jennifer Dennison: Writing-Original draft preparation and Editing, Investigation, Visualization: Samuel Carlson: Writing-Original draft preparation and Editing: Shannon Faehling: Writing-Original draft preparation and Editing: Hannah Phelan: Writing-Review and Editing: Muhammad Tariq: Writing-Review and Editing Ateeq Mubarik: Writing-Review and Editing, Supervision.
Institutional review board statement: Institutional Review Board approval was not necessary for our report.
Funding: None. The authors did not receive grant or outside funding in support of their research or preparation of this manuscript. They did not receive payment or any benefits from commercial entities.Declaration of competing interest
All authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY-NC-ND | 33619439 | 19,173,777 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | Fatal VAP-related pulmonary aspergillosis by Aspergillus niger in a positive COVID-19 patient.
Invasive pulmonary aspergillosis, known as a complication in patients with severe respiratory syndromes, recently showed a correlation with COVID-19 pneumonia, and the clinical characteristics of COVID-19 associated pulmonary aspergillosis (CAPA) have been described. Unfortunately, infections by the Aspergillus genus are often diagnosed in post-mortem time, because of diagnostic delays and a rapid worsening of respiratory conditions. Literature data document, in fact, only few cases of COVID-19 Aspergillus niger coinfection. The aim of this study was to describe a case of a VAP-related probable pulmonary aspergillosis by Aspergillus niger in a COVID-19 patient. Despite the definition of fungal etiology and the rapid administration of antifungal therapy, the patient died while on ventilator support because of severe respiratory impairment.
1 Background
IPA, caused by the Aspergillus genus, is known as a common complication in patients with severe respiratory syndromes and is also related to high mortality rates [1,2]. There are many predisposing factors to the development of IPA, basically recognized in prolonged treatment with corticosteroids and lung epithelial damage [1]. Several cases of IPA have been documented as super-infections in patients with severe respiratory illness such as influenza and MERS-CoV [1,3]. Starting in December 2019 many severe respiratory syndrome cases caused by Coronavirus-19 (SARS-CoV-2) have been diagnosed. The clinical impact of this infection defines a highly dysregulated immune response and diffuse lung damage, which lead to the early onset of secondary infections [2,3]. Here we describe a case of invasive pulmonary aspergillosis by Aspergillus niger in a patient with COVID-19 pneumonia and acute respiratory distress syndrome.
2 Case presentation
In October 2020, a 73-year-old man was admitted to the accident and emergency department of the University Hospital of Catania, Sicily, Italy, reporting fever, cough and diarrhea. Vital signs were recorded as the following: blood pressure of 160/87 mmHg, heart rate of 85 beats per minute, respiratory rate of 40 beats per minute and SPo2 of 78%. A chest X-ray showed bilateral infiltrates (Fig. 1) and a nasopharyngeal swab sample was collected and tested positive for COVID-19 using molecular testing.Fig. 1 Rx-graphic performed in anteroposterior projection and in seated decubitus with a portable device. A parenchymal consolidation is visible in the right-middle lung field. There is also an extended interstitial lung disease with a reticulo-nodular pattern, pronounced pulmonary hilar and free costo-phrenic angles. Cardiac image is enlarged.
Fig. 1
The patient was moved to the ICU with the diagnosis of Coronavirus-19 pneumonia. Clinical history was updated to include a previous diagnosis of diabetes and hypertension. Corticosteroid therapy with dexamethasone (12 mg/day) and C-PAP ventilation were immediately required. In the following days, laboratory tests showed significant increases of white blood cells (up to 30210/mm3) and lactate (up to 864 U/L), and low albumin (down to 2.27 g/dL). There was also a high increase of C-reactive protein up to 101.87 mg/L. On day 4, seric levels of the GM (Platelia Aspergillus; Biorad) and 1,3-β-D-glucan (Fungitell; Associates of Cape Cod Inc., Falmouth, Massachusetts, USA) were prescribed because of the patient's risk factors, which tested negative. On day 10 ventilator support with oro-tracheal intubation was implemented, due to a rapid decline of the patient's consciousness and respiratory quality. Because of a fever episode, antibiotic treatment with meropenem (3g/day) was started and a peripheral blood sample was taken for a microbiological culture, which tested negative. On the same day some surveillance exams were performed: cultures from rectal, nasal and pharyngeal swabs reported a normal microbiota, while a culture from a urinary sample revealed 100000 ufc/ml of Pseudomonas aeruginosa. Because of this positive result the urinary catheter was removed and a therapeutic lavage with antibiotics was carried out, with complete resolution. On day 16 a new chest X-ray was performed that showed a pulmonary worsening (Fig. 2).Fig. 2 Rx-graphic performed in anteroposterior projection and in supine decubitus with a portable device. An extended parenchymal consolidation is visible in left apical, intercleidohilar and hilum-para-hilar point. A shadowed parenchymal consolidation is also visible in the right intercleidohilar point. There is an extended interstitial lung disease with a reticulo-nodular pattern. Because of cardiac image overlapping, the right hilum cannot be evaluated. Left hilum is large and thickened. Right costo-phrenic angles are partially hidden.
Fig. 2
At the same time, new seric dosages were required: β-glucan serum level was 84 pg/mL while galactomannan had a T index of 4.9, suggestive of probable fungal angioinvasion. A bronchoaspirate sample was collected for bacteriological and mycological examinations, because of the persistence of high inflammation indices. For the mycological examination conventional methods by microscopic and fungal culture in Sabouraud's dextrose agar medium supplemented with chloramphenicol and gentamycin were performed. Molecular methods were also used and real-time PCR assay for the detection of Aspergillus was carried out. The AsperGenius® multiplex PCR (PathoNostics, The Netherlands) was used for the detection of the most clinically relevant Aspergillus species. DNA was extracted by using the GenoXtract instrument (Hain Lifescience, Germany) following the manufacturer's instructions. PCR was performed adding 5 μl of DNA extract to the PCR mix and a Rotor-Gene Q (Qiagen) was used for amplification and melting curve analysis. The direct microscopic examination with 15% potassium hydroxide (KOH) showed several hyaline septate hyphae and Aspergillus sp. was detected by PCR. After 72 h of incubation at 32 °C, the growth of numerous colonies was observed (Fig. 3).Fig. 3 (A) Direct examination of bronchoaspirate sample with 15% KOH (original magnification ×40); (B) growth on Sabouraud Dextrose Agar after 72 h at 32 °C.
Fig. 3
Identification of the isolate was performed by standard phenotypic methods, based on macroscopic and microscopic morphological studies. The pathogen was identified as Aspergillus section Nigri. Matrix-assisted laser desorption ionization time of flight mass spectrometry on a Microflex LT (Bruker Daltonics, Bremen, Germany) platform after ethanol-formic acid extraction, identified the isolate as Aspergillus niger (score: 2.155). The same sample reported negative results from bacteriological examinations. Surveillance cultures from oropharyngeal, rectal and nasal swabs also revealed the presence of Aspergillus niger. Susceptibility to fluconazole, itraconazole, voriconazole, posaconazole, flucytosine, caspofungin, anidulafungin, micafungin, and amphotericin B, was evaluated by the Sensititre®YeastOne method. MIC values of >256 μg/mL for fluconazole, 0.25 μg/mL for itraconazole, 1 μg/mL for voriconazole, 0.125 μg/mL for posaconazole, 2 μg/mL for flucytosine, and 0.12 μg/mL for amphotericin B were obtained. Echinocandins presented adequate minimum effective concentration (MEC) values: 0.03 μg/mL for micafungin, 0.015 μg/mL for caspofungin and 0.03 μg/mL for anidulafungin. Results showed various therapeutic options evaluated with dilution ranges and epidemiological cut-offs in the absence of clinical breakpoints [4]. Some literature reports evaluated the effectiveness of isavuconazole against the Aspergillus genus and the reliability of the MIC strip method for its susceptibility test [5,6]. According to these reports, the susceptibility test for isavuconazole was performed using the MIC strip method and showed a MIC value of 2 mg/L. The patient was put on voriconazole 800 mg/day. On day 19, the patient died in the ICU of heart failure, while he was still on ventilator support.
3 Discussion and conclusion
According to recent literature data (June 2020), about 38 cases of COVID-19 associated pulmonary aspergillosis are known [1,2]. Percentages are probably underestimated owing to a diagnostic delay or to the lack of clinical recognition [1]. Most COVID-related pulmonary aspergillosis cases are, in fact, belatedly diagnosed, often in post-mortem time. In our case, because of the patient's critical issues, it was not possible to collect samples from the lower respiratory tract regularly. This inconvenience had a negative impact on the possibility to define a fungal colonization by Aspergillus and on the timeliness of a correct diagnosis of pulmonary aspergillosis. These delays, together with patient's risk factors represented by extensive lung damage and prolonged treatment with corticosteroids [3], involved a rapid worsening of the respiratory condition. The patient also reported a previous diagnosis of diabetes, which is related to structural modifications of blood vessels and predisposes to fungal angioinvasion. To clarify the eventuality of a previous chronic Aspergillus colonization, a detection of Aspergillus-specific antibodies by agar gel immunodiffusion was performed on serum. The negative result leads us to the assumption that the patient, most likely, was infected in a hospital setting during intubation. According to recent data Aspergillus sp. are recognized as a potential cause of VAP in immunocompetent hosts [7,8]. Unfortunately, fungi are often not included among the possible causes of VAP in non-immunocompromised patients with other risk factors and therefore Aspergillus shows its angioinvasive properties for a long period before the real diagnosis of pulmonary aspergillosis [8]. Assuming that the infection of our patient was a VAP-related pulmonary aspergillosis, a frequent check of seric and colonization parameters would have allowed a prompter diagnosis: in the six days between oro-tracheal intubation and diagnosis of pulmonary aspergillosis, we do not have regular reporting of a mycological surveillance for this patient. This omission led to a dangerous consequence: Aspergillus had sufficient time to proliferate and to angioinvade the patient's respiratory tract, therefore the diagnosis and the administration of voriconazole were not enough, also considering the critical status of the pulmonary epithelium. Notwithstanding his critical clinical condition, the patient contrasted the progression of the infection for a brief time, both because of the absence of a marked neutropenia, which is often a predisposing condition to pulmonary aspergillosis and because of the involvement of Aspergillus niger, whose virulent nature is widely confirmed but it is lower when compared to other Aspergillus species. In fact, although Aspergillus niger is able to produce a severe pulmonary disease it is rarely reported as a cause of invasive aspergillosis, while it is often described as the etiological agent of otomycosis and cutaneous infections [9]. Moreover, in a study that investigated the presence of triazole-resistant Aspergillus isolates in agricultural areas in Southern Italy, the presence of other Aspergillus species was reported. These species, although less pathogenic than A. fumigatus, are very frequently isolated in Sicily and can represent a potential cause of invasive disease in patients at risk [10]. Despite the definition of fungal etiology and the rapid administration of voriconazole, the patient died because of the severe impairment of his respiratory condition. Consequently, invasive pulmonary aspergillosis should be investigated as a possible complication in cases of severe respiratory syndromes, even in immunocompetent hosts [11,12]. A rapid diagnosis can lead to the development of an accurate therapeutic plan and probably to clinical remission only if the patient has no comorbidities nor extensive pulmonary damage. Through our experience we suggest adding a study of fungal colonization to the clinical management of all immunocompetent patients with one or more risk factors for the development of invasive fungal infection [13]. Immunocompetent patients with COVID-19 infection should be screened early for microbiological colonization before admission to critical wards, such as ICUs. Colonization data allow a carefully monitoring of the patient and prevention of invasive infections, especially in cases on ventilator support.
Funding
This research received no external funding.
Author contributions
Investigation, Methodology and Writing the original draft of the manuscript: L.T., M.C., and G.M.; Data curation: F.O. and M.A.; Methodology and Supervision: S.O. All authors read and approved the final manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We wish to thank the Scientific Bureau of the 10.13039/501100004505 University of Catania for language support. | DEXAMETHASONE, MEROPENEM, VORICONAZOLE | DrugsGivenReaction | CC BY | 33619451 | 19,773,167 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory disorder'. | Fatal VAP-related pulmonary aspergillosis by Aspergillus niger in a positive COVID-19 patient.
Invasive pulmonary aspergillosis, known as a complication in patients with severe respiratory syndromes, recently showed a correlation with COVID-19 pneumonia, and the clinical characteristics of COVID-19 associated pulmonary aspergillosis (CAPA) have been described. Unfortunately, infections by the Aspergillus genus are often diagnosed in post-mortem time, because of diagnostic delays and a rapid worsening of respiratory conditions. Literature data document, in fact, only few cases of COVID-19 Aspergillus niger coinfection. The aim of this study was to describe a case of a VAP-related probable pulmonary aspergillosis by Aspergillus niger in a COVID-19 patient. Despite the definition of fungal etiology and the rapid administration of antifungal therapy, the patient died while on ventilator support because of severe respiratory impairment.
1 Background
IPA, caused by the Aspergillus genus, is known as a common complication in patients with severe respiratory syndromes and is also related to high mortality rates [1,2]. There are many predisposing factors to the development of IPA, basically recognized in prolonged treatment with corticosteroids and lung epithelial damage [1]. Several cases of IPA have been documented as super-infections in patients with severe respiratory illness such as influenza and MERS-CoV [1,3]. Starting in December 2019 many severe respiratory syndrome cases caused by Coronavirus-19 (SARS-CoV-2) have been diagnosed. The clinical impact of this infection defines a highly dysregulated immune response and diffuse lung damage, which lead to the early onset of secondary infections [2,3]. Here we describe a case of invasive pulmonary aspergillosis by Aspergillus niger in a patient with COVID-19 pneumonia and acute respiratory distress syndrome.
2 Case presentation
In October 2020, a 73-year-old man was admitted to the accident and emergency department of the University Hospital of Catania, Sicily, Italy, reporting fever, cough and diarrhea. Vital signs were recorded as the following: blood pressure of 160/87 mmHg, heart rate of 85 beats per minute, respiratory rate of 40 beats per minute and SPo2 of 78%. A chest X-ray showed bilateral infiltrates (Fig. 1) and a nasopharyngeal swab sample was collected and tested positive for COVID-19 using molecular testing.Fig. 1 Rx-graphic performed in anteroposterior projection and in seated decubitus with a portable device. A parenchymal consolidation is visible in the right-middle lung field. There is also an extended interstitial lung disease with a reticulo-nodular pattern, pronounced pulmonary hilar and free costo-phrenic angles. Cardiac image is enlarged.
Fig. 1
The patient was moved to the ICU with the diagnosis of Coronavirus-19 pneumonia. Clinical history was updated to include a previous diagnosis of diabetes and hypertension. Corticosteroid therapy with dexamethasone (12 mg/day) and C-PAP ventilation were immediately required. In the following days, laboratory tests showed significant increases of white blood cells (up to 30210/mm3) and lactate (up to 864 U/L), and low albumin (down to 2.27 g/dL). There was also a high increase of C-reactive protein up to 101.87 mg/L. On day 4, seric levels of the GM (Platelia Aspergillus; Biorad) and 1,3-β-D-glucan (Fungitell; Associates of Cape Cod Inc., Falmouth, Massachusetts, USA) were prescribed because of the patient's risk factors, which tested negative. On day 10 ventilator support with oro-tracheal intubation was implemented, due to a rapid decline of the patient's consciousness and respiratory quality. Because of a fever episode, antibiotic treatment with meropenem (3g/day) was started and a peripheral blood sample was taken for a microbiological culture, which tested negative. On the same day some surveillance exams were performed: cultures from rectal, nasal and pharyngeal swabs reported a normal microbiota, while a culture from a urinary sample revealed 100000 ufc/ml of Pseudomonas aeruginosa. Because of this positive result the urinary catheter was removed and a therapeutic lavage with antibiotics was carried out, with complete resolution. On day 16 a new chest X-ray was performed that showed a pulmonary worsening (Fig. 2).Fig. 2 Rx-graphic performed in anteroposterior projection and in supine decubitus with a portable device. An extended parenchymal consolidation is visible in left apical, intercleidohilar and hilum-para-hilar point. A shadowed parenchymal consolidation is also visible in the right intercleidohilar point. There is an extended interstitial lung disease with a reticulo-nodular pattern. Because of cardiac image overlapping, the right hilum cannot be evaluated. Left hilum is large and thickened. Right costo-phrenic angles are partially hidden.
Fig. 2
At the same time, new seric dosages were required: β-glucan serum level was 84 pg/mL while galactomannan had a T index of 4.9, suggestive of probable fungal angioinvasion. A bronchoaspirate sample was collected for bacteriological and mycological examinations, because of the persistence of high inflammation indices. For the mycological examination conventional methods by microscopic and fungal culture in Sabouraud's dextrose agar medium supplemented with chloramphenicol and gentamycin were performed. Molecular methods were also used and real-time PCR assay for the detection of Aspergillus was carried out. The AsperGenius® multiplex PCR (PathoNostics, The Netherlands) was used for the detection of the most clinically relevant Aspergillus species. DNA was extracted by using the GenoXtract instrument (Hain Lifescience, Germany) following the manufacturer's instructions. PCR was performed adding 5 μl of DNA extract to the PCR mix and a Rotor-Gene Q (Qiagen) was used for amplification and melting curve analysis. The direct microscopic examination with 15% potassium hydroxide (KOH) showed several hyaline septate hyphae and Aspergillus sp. was detected by PCR. After 72 h of incubation at 32 °C, the growth of numerous colonies was observed (Fig. 3).Fig. 3 (A) Direct examination of bronchoaspirate sample with 15% KOH (original magnification ×40); (B) growth on Sabouraud Dextrose Agar after 72 h at 32 °C.
Fig. 3
Identification of the isolate was performed by standard phenotypic methods, based on macroscopic and microscopic morphological studies. The pathogen was identified as Aspergillus section Nigri. Matrix-assisted laser desorption ionization time of flight mass spectrometry on a Microflex LT (Bruker Daltonics, Bremen, Germany) platform after ethanol-formic acid extraction, identified the isolate as Aspergillus niger (score: 2.155). The same sample reported negative results from bacteriological examinations. Surveillance cultures from oropharyngeal, rectal and nasal swabs also revealed the presence of Aspergillus niger. Susceptibility to fluconazole, itraconazole, voriconazole, posaconazole, flucytosine, caspofungin, anidulafungin, micafungin, and amphotericin B, was evaluated by the Sensititre®YeastOne method. MIC values of >256 μg/mL for fluconazole, 0.25 μg/mL for itraconazole, 1 μg/mL for voriconazole, 0.125 μg/mL for posaconazole, 2 μg/mL for flucytosine, and 0.12 μg/mL for amphotericin B were obtained. Echinocandins presented adequate minimum effective concentration (MEC) values: 0.03 μg/mL for micafungin, 0.015 μg/mL for caspofungin and 0.03 μg/mL for anidulafungin. Results showed various therapeutic options evaluated with dilution ranges and epidemiological cut-offs in the absence of clinical breakpoints [4]. Some literature reports evaluated the effectiveness of isavuconazole against the Aspergillus genus and the reliability of the MIC strip method for its susceptibility test [5,6]. According to these reports, the susceptibility test for isavuconazole was performed using the MIC strip method and showed a MIC value of 2 mg/L. The patient was put on voriconazole 800 mg/day. On day 19, the patient died in the ICU of heart failure, while he was still on ventilator support.
3 Discussion and conclusion
According to recent literature data (June 2020), about 38 cases of COVID-19 associated pulmonary aspergillosis are known [1,2]. Percentages are probably underestimated owing to a diagnostic delay or to the lack of clinical recognition [1]. Most COVID-related pulmonary aspergillosis cases are, in fact, belatedly diagnosed, often in post-mortem time. In our case, because of the patient's critical issues, it was not possible to collect samples from the lower respiratory tract regularly. This inconvenience had a negative impact on the possibility to define a fungal colonization by Aspergillus and on the timeliness of a correct diagnosis of pulmonary aspergillosis. These delays, together with patient's risk factors represented by extensive lung damage and prolonged treatment with corticosteroids [3], involved a rapid worsening of the respiratory condition. The patient also reported a previous diagnosis of diabetes, which is related to structural modifications of blood vessels and predisposes to fungal angioinvasion. To clarify the eventuality of a previous chronic Aspergillus colonization, a detection of Aspergillus-specific antibodies by agar gel immunodiffusion was performed on serum. The negative result leads us to the assumption that the patient, most likely, was infected in a hospital setting during intubation. According to recent data Aspergillus sp. are recognized as a potential cause of VAP in immunocompetent hosts [7,8]. Unfortunately, fungi are often not included among the possible causes of VAP in non-immunocompromised patients with other risk factors and therefore Aspergillus shows its angioinvasive properties for a long period before the real diagnosis of pulmonary aspergillosis [8]. Assuming that the infection of our patient was a VAP-related pulmonary aspergillosis, a frequent check of seric and colonization parameters would have allowed a prompter diagnosis: in the six days between oro-tracheal intubation and diagnosis of pulmonary aspergillosis, we do not have regular reporting of a mycological surveillance for this patient. This omission led to a dangerous consequence: Aspergillus had sufficient time to proliferate and to angioinvade the patient's respiratory tract, therefore the diagnosis and the administration of voriconazole were not enough, also considering the critical status of the pulmonary epithelium. Notwithstanding his critical clinical condition, the patient contrasted the progression of the infection for a brief time, both because of the absence of a marked neutropenia, which is often a predisposing condition to pulmonary aspergillosis and because of the involvement of Aspergillus niger, whose virulent nature is widely confirmed but it is lower when compared to other Aspergillus species. In fact, although Aspergillus niger is able to produce a severe pulmonary disease it is rarely reported as a cause of invasive aspergillosis, while it is often described as the etiological agent of otomycosis and cutaneous infections [9]. Moreover, in a study that investigated the presence of triazole-resistant Aspergillus isolates in agricultural areas in Southern Italy, the presence of other Aspergillus species was reported. These species, although less pathogenic than A. fumigatus, are very frequently isolated in Sicily and can represent a potential cause of invasive disease in patients at risk [10]. Despite the definition of fungal etiology and the rapid administration of voriconazole, the patient died because of the severe impairment of his respiratory condition. Consequently, invasive pulmonary aspergillosis should be investigated as a possible complication in cases of severe respiratory syndromes, even in immunocompetent hosts [11,12]. A rapid diagnosis can lead to the development of an accurate therapeutic plan and probably to clinical remission only if the patient has no comorbidities nor extensive pulmonary damage. Through our experience we suggest adding a study of fungal colonization to the clinical management of all immunocompetent patients with one or more risk factors for the development of invasive fungal infection [13]. Immunocompetent patients with COVID-19 infection should be screened early for microbiological colonization before admission to critical wards, such as ICUs. Colonization data allow a carefully monitoring of the patient and prevention of invasive infections, especially in cases on ventilator support.
Funding
This research received no external funding.
Author contributions
Investigation, Methodology and Writing the original draft of the manuscript: L.T., M.C., and G.M.; Data curation: F.O. and M.A.; Methodology and Supervision: S.O. All authors read and approved the final manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We wish to thank the Scientific Bureau of the 10.13039/501100004505 University of Catania for language support. | DEXAMETHASONE, MEROPENEM, VORICONAZOLE | DrugsGivenReaction | CC BY | 33619451 | 19,773,167 | 2021 |
What was the outcome of reaction 'Cardiac failure'? | Fatal VAP-related pulmonary aspergillosis by Aspergillus niger in a positive COVID-19 patient.
Invasive pulmonary aspergillosis, known as a complication in patients with severe respiratory syndromes, recently showed a correlation with COVID-19 pneumonia, and the clinical characteristics of COVID-19 associated pulmonary aspergillosis (CAPA) have been described. Unfortunately, infections by the Aspergillus genus are often diagnosed in post-mortem time, because of diagnostic delays and a rapid worsening of respiratory conditions. Literature data document, in fact, only few cases of COVID-19 Aspergillus niger coinfection. The aim of this study was to describe a case of a VAP-related probable pulmonary aspergillosis by Aspergillus niger in a COVID-19 patient. Despite the definition of fungal etiology and the rapid administration of antifungal therapy, the patient died while on ventilator support because of severe respiratory impairment.
1 Background
IPA, caused by the Aspergillus genus, is known as a common complication in patients with severe respiratory syndromes and is also related to high mortality rates [1,2]. There are many predisposing factors to the development of IPA, basically recognized in prolonged treatment with corticosteroids and lung epithelial damage [1]. Several cases of IPA have been documented as super-infections in patients with severe respiratory illness such as influenza and MERS-CoV [1,3]. Starting in December 2019 many severe respiratory syndrome cases caused by Coronavirus-19 (SARS-CoV-2) have been diagnosed. The clinical impact of this infection defines a highly dysregulated immune response and diffuse lung damage, which lead to the early onset of secondary infections [2,3]. Here we describe a case of invasive pulmonary aspergillosis by Aspergillus niger in a patient with COVID-19 pneumonia and acute respiratory distress syndrome.
2 Case presentation
In October 2020, a 73-year-old man was admitted to the accident and emergency department of the University Hospital of Catania, Sicily, Italy, reporting fever, cough and diarrhea. Vital signs were recorded as the following: blood pressure of 160/87 mmHg, heart rate of 85 beats per minute, respiratory rate of 40 beats per minute and SPo2 of 78%. A chest X-ray showed bilateral infiltrates (Fig. 1) and a nasopharyngeal swab sample was collected and tested positive for COVID-19 using molecular testing.Fig. 1 Rx-graphic performed in anteroposterior projection and in seated decubitus with a portable device. A parenchymal consolidation is visible in the right-middle lung field. There is also an extended interstitial lung disease with a reticulo-nodular pattern, pronounced pulmonary hilar and free costo-phrenic angles. Cardiac image is enlarged.
Fig. 1
The patient was moved to the ICU with the diagnosis of Coronavirus-19 pneumonia. Clinical history was updated to include a previous diagnosis of diabetes and hypertension. Corticosteroid therapy with dexamethasone (12 mg/day) and C-PAP ventilation were immediately required. In the following days, laboratory tests showed significant increases of white blood cells (up to 30210/mm3) and lactate (up to 864 U/L), and low albumin (down to 2.27 g/dL). There was also a high increase of C-reactive protein up to 101.87 mg/L. On day 4, seric levels of the GM (Platelia Aspergillus; Biorad) and 1,3-β-D-glucan (Fungitell; Associates of Cape Cod Inc., Falmouth, Massachusetts, USA) were prescribed because of the patient's risk factors, which tested negative. On day 10 ventilator support with oro-tracheal intubation was implemented, due to a rapid decline of the patient's consciousness and respiratory quality. Because of a fever episode, antibiotic treatment with meropenem (3g/day) was started and a peripheral blood sample was taken for a microbiological culture, which tested negative. On the same day some surveillance exams were performed: cultures from rectal, nasal and pharyngeal swabs reported a normal microbiota, while a culture from a urinary sample revealed 100000 ufc/ml of Pseudomonas aeruginosa. Because of this positive result the urinary catheter was removed and a therapeutic lavage with antibiotics was carried out, with complete resolution. On day 16 a new chest X-ray was performed that showed a pulmonary worsening (Fig. 2).Fig. 2 Rx-graphic performed in anteroposterior projection and in supine decubitus with a portable device. An extended parenchymal consolidation is visible in left apical, intercleidohilar and hilum-para-hilar point. A shadowed parenchymal consolidation is also visible in the right intercleidohilar point. There is an extended interstitial lung disease with a reticulo-nodular pattern. Because of cardiac image overlapping, the right hilum cannot be evaluated. Left hilum is large and thickened. Right costo-phrenic angles are partially hidden.
Fig. 2
At the same time, new seric dosages were required: β-glucan serum level was 84 pg/mL while galactomannan had a T index of 4.9, suggestive of probable fungal angioinvasion. A bronchoaspirate sample was collected for bacteriological and mycological examinations, because of the persistence of high inflammation indices. For the mycological examination conventional methods by microscopic and fungal culture in Sabouraud's dextrose agar medium supplemented with chloramphenicol and gentamycin were performed. Molecular methods were also used and real-time PCR assay for the detection of Aspergillus was carried out. The AsperGenius® multiplex PCR (PathoNostics, The Netherlands) was used for the detection of the most clinically relevant Aspergillus species. DNA was extracted by using the GenoXtract instrument (Hain Lifescience, Germany) following the manufacturer's instructions. PCR was performed adding 5 μl of DNA extract to the PCR mix and a Rotor-Gene Q (Qiagen) was used for amplification and melting curve analysis. The direct microscopic examination with 15% potassium hydroxide (KOH) showed several hyaline septate hyphae and Aspergillus sp. was detected by PCR. After 72 h of incubation at 32 °C, the growth of numerous colonies was observed (Fig. 3).Fig. 3 (A) Direct examination of bronchoaspirate sample with 15% KOH (original magnification ×40); (B) growth on Sabouraud Dextrose Agar after 72 h at 32 °C.
Fig. 3
Identification of the isolate was performed by standard phenotypic methods, based on macroscopic and microscopic morphological studies. The pathogen was identified as Aspergillus section Nigri. Matrix-assisted laser desorption ionization time of flight mass spectrometry on a Microflex LT (Bruker Daltonics, Bremen, Germany) platform after ethanol-formic acid extraction, identified the isolate as Aspergillus niger (score: 2.155). The same sample reported negative results from bacteriological examinations. Surveillance cultures from oropharyngeal, rectal and nasal swabs also revealed the presence of Aspergillus niger. Susceptibility to fluconazole, itraconazole, voriconazole, posaconazole, flucytosine, caspofungin, anidulafungin, micafungin, and amphotericin B, was evaluated by the Sensititre®YeastOne method. MIC values of >256 μg/mL for fluconazole, 0.25 μg/mL for itraconazole, 1 μg/mL for voriconazole, 0.125 μg/mL for posaconazole, 2 μg/mL for flucytosine, and 0.12 μg/mL for amphotericin B were obtained. Echinocandins presented adequate minimum effective concentration (MEC) values: 0.03 μg/mL for micafungin, 0.015 μg/mL for caspofungin and 0.03 μg/mL for anidulafungin. Results showed various therapeutic options evaluated with dilution ranges and epidemiological cut-offs in the absence of clinical breakpoints [4]. Some literature reports evaluated the effectiveness of isavuconazole against the Aspergillus genus and the reliability of the MIC strip method for its susceptibility test [5,6]. According to these reports, the susceptibility test for isavuconazole was performed using the MIC strip method and showed a MIC value of 2 mg/L. The patient was put on voriconazole 800 mg/day. On day 19, the patient died in the ICU of heart failure, while he was still on ventilator support.
3 Discussion and conclusion
According to recent literature data (June 2020), about 38 cases of COVID-19 associated pulmonary aspergillosis are known [1,2]. Percentages are probably underestimated owing to a diagnostic delay or to the lack of clinical recognition [1]. Most COVID-related pulmonary aspergillosis cases are, in fact, belatedly diagnosed, often in post-mortem time. In our case, because of the patient's critical issues, it was not possible to collect samples from the lower respiratory tract regularly. This inconvenience had a negative impact on the possibility to define a fungal colonization by Aspergillus and on the timeliness of a correct diagnosis of pulmonary aspergillosis. These delays, together with patient's risk factors represented by extensive lung damage and prolonged treatment with corticosteroids [3], involved a rapid worsening of the respiratory condition. The patient also reported a previous diagnosis of diabetes, which is related to structural modifications of blood vessels and predisposes to fungal angioinvasion. To clarify the eventuality of a previous chronic Aspergillus colonization, a detection of Aspergillus-specific antibodies by agar gel immunodiffusion was performed on serum. The negative result leads us to the assumption that the patient, most likely, was infected in a hospital setting during intubation. According to recent data Aspergillus sp. are recognized as a potential cause of VAP in immunocompetent hosts [7,8]. Unfortunately, fungi are often not included among the possible causes of VAP in non-immunocompromised patients with other risk factors and therefore Aspergillus shows its angioinvasive properties for a long period before the real diagnosis of pulmonary aspergillosis [8]. Assuming that the infection of our patient was a VAP-related pulmonary aspergillosis, a frequent check of seric and colonization parameters would have allowed a prompter diagnosis: in the six days between oro-tracheal intubation and diagnosis of pulmonary aspergillosis, we do not have regular reporting of a mycological surveillance for this patient. This omission led to a dangerous consequence: Aspergillus had sufficient time to proliferate and to angioinvade the patient's respiratory tract, therefore the diagnosis and the administration of voriconazole were not enough, also considering the critical status of the pulmonary epithelium. Notwithstanding his critical clinical condition, the patient contrasted the progression of the infection for a brief time, both because of the absence of a marked neutropenia, which is often a predisposing condition to pulmonary aspergillosis and because of the involvement of Aspergillus niger, whose virulent nature is widely confirmed but it is lower when compared to other Aspergillus species. In fact, although Aspergillus niger is able to produce a severe pulmonary disease it is rarely reported as a cause of invasive aspergillosis, while it is often described as the etiological agent of otomycosis and cutaneous infections [9]. Moreover, in a study that investigated the presence of triazole-resistant Aspergillus isolates in agricultural areas in Southern Italy, the presence of other Aspergillus species was reported. These species, although less pathogenic than A. fumigatus, are very frequently isolated in Sicily and can represent a potential cause of invasive disease in patients at risk [10]. Despite the definition of fungal etiology and the rapid administration of voriconazole, the patient died because of the severe impairment of his respiratory condition. Consequently, invasive pulmonary aspergillosis should be investigated as a possible complication in cases of severe respiratory syndromes, even in immunocompetent hosts [11,12]. A rapid diagnosis can lead to the development of an accurate therapeutic plan and probably to clinical remission only if the patient has no comorbidities nor extensive pulmonary damage. Through our experience we suggest adding a study of fungal colonization to the clinical management of all immunocompetent patients with one or more risk factors for the development of invasive fungal infection [13]. Immunocompetent patients with COVID-19 infection should be screened early for microbiological colonization before admission to critical wards, such as ICUs. Colonization data allow a carefully monitoring of the patient and prevention of invasive infections, especially in cases on ventilator support.
Funding
This research received no external funding.
Author contributions
Investigation, Methodology and Writing the original draft of the manuscript: L.T., M.C., and G.M.; Data curation: F.O. and M.A.; Methodology and Supervision: S.O. All authors read and approved the final manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We wish to thank the Scientific Bureau of the 10.13039/501100004505 University of Catania for language support. | Fatal | ReactionOutcome | CC BY | 33619451 | 19,773,167 | 2021 |
What was the outcome of reaction 'Respiratory disorder'? | Fatal VAP-related pulmonary aspergillosis by Aspergillus niger in a positive COVID-19 patient.
Invasive pulmonary aspergillosis, known as a complication in patients with severe respiratory syndromes, recently showed a correlation with COVID-19 pneumonia, and the clinical characteristics of COVID-19 associated pulmonary aspergillosis (CAPA) have been described. Unfortunately, infections by the Aspergillus genus are often diagnosed in post-mortem time, because of diagnostic delays and a rapid worsening of respiratory conditions. Literature data document, in fact, only few cases of COVID-19 Aspergillus niger coinfection. The aim of this study was to describe a case of a VAP-related probable pulmonary aspergillosis by Aspergillus niger in a COVID-19 patient. Despite the definition of fungal etiology and the rapid administration of antifungal therapy, the patient died while on ventilator support because of severe respiratory impairment.
1 Background
IPA, caused by the Aspergillus genus, is known as a common complication in patients with severe respiratory syndromes and is also related to high mortality rates [1,2]. There are many predisposing factors to the development of IPA, basically recognized in prolonged treatment with corticosteroids and lung epithelial damage [1]. Several cases of IPA have been documented as super-infections in patients with severe respiratory illness such as influenza and MERS-CoV [1,3]. Starting in December 2019 many severe respiratory syndrome cases caused by Coronavirus-19 (SARS-CoV-2) have been diagnosed. The clinical impact of this infection defines a highly dysregulated immune response and diffuse lung damage, which lead to the early onset of secondary infections [2,3]. Here we describe a case of invasive pulmonary aspergillosis by Aspergillus niger in a patient with COVID-19 pneumonia and acute respiratory distress syndrome.
2 Case presentation
In October 2020, a 73-year-old man was admitted to the accident and emergency department of the University Hospital of Catania, Sicily, Italy, reporting fever, cough and diarrhea. Vital signs were recorded as the following: blood pressure of 160/87 mmHg, heart rate of 85 beats per minute, respiratory rate of 40 beats per minute and SPo2 of 78%. A chest X-ray showed bilateral infiltrates (Fig. 1) and a nasopharyngeal swab sample was collected and tested positive for COVID-19 using molecular testing.Fig. 1 Rx-graphic performed in anteroposterior projection and in seated decubitus with a portable device. A parenchymal consolidation is visible in the right-middle lung field. There is also an extended interstitial lung disease with a reticulo-nodular pattern, pronounced pulmonary hilar and free costo-phrenic angles. Cardiac image is enlarged.
Fig. 1
The patient was moved to the ICU with the diagnosis of Coronavirus-19 pneumonia. Clinical history was updated to include a previous diagnosis of diabetes and hypertension. Corticosteroid therapy with dexamethasone (12 mg/day) and C-PAP ventilation were immediately required. In the following days, laboratory tests showed significant increases of white blood cells (up to 30210/mm3) and lactate (up to 864 U/L), and low albumin (down to 2.27 g/dL). There was also a high increase of C-reactive protein up to 101.87 mg/L. On day 4, seric levels of the GM (Platelia Aspergillus; Biorad) and 1,3-β-D-glucan (Fungitell; Associates of Cape Cod Inc., Falmouth, Massachusetts, USA) were prescribed because of the patient's risk factors, which tested negative. On day 10 ventilator support with oro-tracheal intubation was implemented, due to a rapid decline of the patient's consciousness and respiratory quality. Because of a fever episode, antibiotic treatment with meropenem (3g/day) was started and a peripheral blood sample was taken for a microbiological culture, which tested negative. On the same day some surveillance exams were performed: cultures from rectal, nasal and pharyngeal swabs reported a normal microbiota, while a culture from a urinary sample revealed 100000 ufc/ml of Pseudomonas aeruginosa. Because of this positive result the urinary catheter was removed and a therapeutic lavage with antibiotics was carried out, with complete resolution. On day 16 a new chest X-ray was performed that showed a pulmonary worsening (Fig. 2).Fig. 2 Rx-graphic performed in anteroposterior projection and in supine decubitus with a portable device. An extended parenchymal consolidation is visible in left apical, intercleidohilar and hilum-para-hilar point. A shadowed parenchymal consolidation is also visible in the right intercleidohilar point. There is an extended interstitial lung disease with a reticulo-nodular pattern. Because of cardiac image overlapping, the right hilum cannot be evaluated. Left hilum is large and thickened. Right costo-phrenic angles are partially hidden.
Fig. 2
At the same time, new seric dosages were required: β-glucan serum level was 84 pg/mL while galactomannan had a T index of 4.9, suggestive of probable fungal angioinvasion. A bronchoaspirate sample was collected for bacteriological and mycological examinations, because of the persistence of high inflammation indices. For the mycological examination conventional methods by microscopic and fungal culture in Sabouraud's dextrose agar medium supplemented with chloramphenicol and gentamycin were performed. Molecular methods were also used and real-time PCR assay for the detection of Aspergillus was carried out. The AsperGenius® multiplex PCR (PathoNostics, The Netherlands) was used for the detection of the most clinically relevant Aspergillus species. DNA was extracted by using the GenoXtract instrument (Hain Lifescience, Germany) following the manufacturer's instructions. PCR was performed adding 5 μl of DNA extract to the PCR mix and a Rotor-Gene Q (Qiagen) was used for amplification and melting curve analysis. The direct microscopic examination with 15% potassium hydroxide (KOH) showed several hyaline septate hyphae and Aspergillus sp. was detected by PCR. After 72 h of incubation at 32 °C, the growth of numerous colonies was observed (Fig. 3).Fig. 3 (A) Direct examination of bronchoaspirate sample with 15% KOH (original magnification ×40); (B) growth on Sabouraud Dextrose Agar after 72 h at 32 °C.
Fig. 3
Identification of the isolate was performed by standard phenotypic methods, based on macroscopic and microscopic morphological studies. The pathogen was identified as Aspergillus section Nigri. Matrix-assisted laser desorption ionization time of flight mass spectrometry on a Microflex LT (Bruker Daltonics, Bremen, Germany) platform after ethanol-formic acid extraction, identified the isolate as Aspergillus niger (score: 2.155). The same sample reported negative results from bacteriological examinations. Surveillance cultures from oropharyngeal, rectal and nasal swabs also revealed the presence of Aspergillus niger. Susceptibility to fluconazole, itraconazole, voriconazole, posaconazole, flucytosine, caspofungin, anidulafungin, micafungin, and amphotericin B, was evaluated by the Sensititre®YeastOne method. MIC values of >256 μg/mL for fluconazole, 0.25 μg/mL for itraconazole, 1 μg/mL for voriconazole, 0.125 μg/mL for posaconazole, 2 μg/mL for flucytosine, and 0.12 μg/mL for amphotericin B were obtained. Echinocandins presented adequate minimum effective concentration (MEC) values: 0.03 μg/mL for micafungin, 0.015 μg/mL for caspofungin and 0.03 μg/mL for anidulafungin. Results showed various therapeutic options evaluated with dilution ranges and epidemiological cut-offs in the absence of clinical breakpoints [4]. Some literature reports evaluated the effectiveness of isavuconazole against the Aspergillus genus and the reliability of the MIC strip method for its susceptibility test [5,6]. According to these reports, the susceptibility test for isavuconazole was performed using the MIC strip method and showed a MIC value of 2 mg/L. The patient was put on voriconazole 800 mg/day. On day 19, the patient died in the ICU of heart failure, while he was still on ventilator support.
3 Discussion and conclusion
According to recent literature data (June 2020), about 38 cases of COVID-19 associated pulmonary aspergillosis are known [1,2]. Percentages are probably underestimated owing to a diagnostic delay or to the lack of clinical recognition [1]. Most COVID-related pulmonary aspergillosis cases are, in fact, belatedly diagnosed, often in post-mortem time. In our case, because of the patient's critical issues, it was not possible to collect samples from the lower respiratory tract regularly. This inconvenience had a negative impact on the possibility to define a fungal colonization by Aspergillus and on the timeliness of a correct diagnosis of pulmonary aspergillosis. These delays, together with patient's risk factors represented by extensive lung damage and prolonged treatment with corticosteroids [3], involved a rapid worsening of the respiratory condition. The patient also reported a previous diagnosis of diabetes, which is related to structural modifications of blood vessels and predisposes to fungal angioinvasion. To clarify the eventuality of a previous chronic Aspergillus colonization, a detection of Aspergillus-specific antibodies by agar gel immunodiffusion was performed on serum. The negative result leads us to the assumption that the patient, most likely, was infected in a hospital setting during intubation. According to recent data Aspergillus sp. are recognized as a potential cause of VAP in immunocompetent hosts [7,8]. Unfortunately, fungi are often not included among the possible causes of VAP in non-immunocompromised patients with other risk factors and therefore Aspergillus shows its angioinvasive properties for a long period before the real diagnosis of pulmonary aspergillosis [8]. Assuming that the infection of our patient was a VAP-related pulmonary aspergillosis, a frequent check of seric and colonization parameters would have allowed a prompter diagnosis: in the six days between oro-tracheal intubation and diagnosis of pulmonary aspergillosis, we do not have regular reporting of a mycological surveillance for this patient. This omission led to a dangerous consequence: Aspergillus had sufficient time to proliferate and to angioinvade the patient's respiratory tract, therefore the diagnosis and the administration of voriconazole were not enough, also considering the critical status of the pulmonary epithelium. Notwithstanding his critical clinical condition, the patient contrasted the progression of the infection for a brief time, both because of the absence of a marked neutropenia, which is often a predisposing condition to pulmonary aspergillosis and because of the involvement of Aspergillus niger, whose virulent nature is widely confirmed but it is lower when compared to other Aspergillus species. In fact, although Aspergillus niger is able to produce a severe pulmonary disease it is rarely reported as a cause of invasive aspergillosis, while it is often described as the etiological agent of otomycosis and cutaneous infections [9]. Moreover, in a study that investigated the presence of triazole-resistant Aspergillus isolates in agricultural areas in Southern Italy, the presence of other Aspergillus species was reported. These species, although less pathogenic than A. fumigatus, are very frequently isolated in Sicily and can represent a potential cause of invasive disease in patients at risk [10]. Despite the definition of fungal etiology and the rapid administration of voriconazole, the patient died because of the severe impairment of his respiratory condition. Consequently, invasive pulmonary aspergillosis should be investigated as a possible complication in cases of severe respiratory syndromes, even in immunocompetent hosts [11,12]. A rapid diagnosis can lead to the development of an accurate therapeutic plan and probably to clinical remission only if the patient has no comorbidities nor extensive pulmonary damage. Through our experience we suggest adding a study of fungal colonization to the clinical management of all immunocompetent patients with one or more risk factors for the development of invasive fungal infection [13]. Immunocompetent patients with COVID-19 infection should be screened early for microbiological colonization before admission to critical wards, such as ICUs. Colonization data allow a carefully monitoring of the patient and prevention of invasive infections, especially in cases on ventilator support.
Funding
This research received no external funding.
Author contributions
Investigation, Methodology and Writing the original draft of the manuscript: L.T., M.C., and G.M.; Data curation: F.O. and M.A.; Methodology and Supervision: S.O. All authors read and approved the final manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We wish to thank the Scientific Bureau of the 10.13039/501100004505 University of Catania for language support. | Fatal | ReactionOutcome | CC BY | 33619451 | 19,773,167 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Real world clinicopathologic observations of patients with metastatic solid tumors receiving immune checkpoint inhibitor therapy: Analysis from Kentucky Cancer Registry.
The state of Kentucky has the highest cancer incidence and mortality in the United States. High-risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution. Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure was 78.3% and 14.5%, respectively. TP53 (62.3%), CDKN1B/2A (40.5%), NOTCH and PIK3 (33.3%) were the most common alterations in tumors. 67.4% were PDL1 positive and 59.4% had intermediate-high tumor mutational burden (TMB). Median TMB (12.6) was twofold to fourfold compared to clinical trials. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway mutations was higher compared to historic cohorts. PDL1 expression had no significant effect on radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended toward statistical significance (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). Median PFS was higher in the high-TMB cohort compared to low-intermediate TMB (median not reached vs. 26 weeks; HR = 0.37. 95%CI 0.13, 1.05). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). This was independent of tumor mutational burden (TMB) status or PDL1 expression status. PIK3 mutants had a higher overall response rate than the wild type (69.6% vs. 43.5%, OR 0.34; p = 0.045). The results should prompt further evaluation of these potential biomarkers and more widespread real-world data publications which might help determine biomarkers that could benefit specific populations.
1 BACKGROUND
Kentucky has the highest cancer incidence and mortality rates in the country with mortality rates nearly 50% higher than the national average. 1 Although this has been mainly attributed to the high‐smoking prevalence in the state, economic, and health care disparities, and genetic factors also play a key role. High‐risk populations such as this are often underrepresented in clinical trials. This could be the reason behind variation of smoking status, predictive biomarkers and tumor genomic alteration between real‐world and clinical trials. 2
Immune checkpoint inhibitors (ICI) were developed to counter the upregulation of immune checkpoints by tumors by targeting programmed cell death protein (PD‐1)/programmed death‐ligand 1 (PDL‐1) or common T lymphocyte antigen‐4 (CTLA‐4), resulting in recognition and killing of tumor cells by the host immune system. There are over two dozen FDA‐approved indications for this class of drugs currently, and they are being increasingly studied in various clinical trials, gradually broadening indications. With accumulating data, it has become clear that the treatment benefits are not homogenous among all the patients. Response rates to single‐agent PD‐1/PDL‐1 inhibitors are variable with 40% in melanoma, 25% in non‐small cell lung cancer (NSCLC), and 19% in renal cell carcinoma. 3 , 4 , 5 , 6 , 7 This highlights the importance of finding a discriminating biomarker that could predict the outcomes of ICI therapy. PDL1 expression, microsatellite instability status, tumor mutation burden, CD8+ T cell infiltration are some of the extensively studied predictive biomarkers; however, with conflicting data in different studies. 8 , 9 The variation in patient selection criteria, assays and determinants used to assess PDL1 expression could have contributed to this discrepancy. 10 Immune‐related adverse events (iRAEs) from ICI therapy affect patients differently, and it is critical to understand its determinants. Evaluation of the current conflicting data on the association between the incidence of iRAEs and response to ICI is equally essential. 11 , 12 Most importantly, there is a lack of real‐world data on response to ICI response and patient outcomes in diverse populations. Real‐world datasets, which reveal genomic profiling and clinical outcomes, provide an important tool to recognize inferences on biomarkers of response and resistance. These data could also enable the discovery of novel biomarkers not be seen in the highly selective clinical trials. Randomized controlled trials with strict entry requirements to guarantee internal stability can lead to the loss of external scalability. This could be due to the exclusion of patients with poor prognosis, older patients, patients with brain metastases, and an ECOG score of 2 or more. Mutational analyses have now enabled subclassification of tumors into molecularly defined subtypes. Evaluation of ICI response and resistance in tumors that demonstrate these mutations is a muddy landscape with little valuable data.
Our study aims to assess various molecular markers and their impact on progression‐free survival and radiological response rates with ICI therapy. This assessment is especially important in our population as Kentucky has an exceedingly high‐smoking prevalence of 24.6% among adults and has the highest incidence of cancer in the United States. This population could present a varied biomarker profile and responses compared to that seen in clinical trials and provide insight into new biomarkers. In recent studies, a higher tumor mutational burden was identified among patients who smoke, with the possibility of smoking‐specific mutations as drivers for oncogenesis. 13 Although the results might not be generalizable, they can give potential information to further search for biomarkers and help identify specific signatures in this high‐risk population.
2 METHODOLOGY
We conducted a retrospective analysis of all patients with metastatic solid tumors above 18 years of age who received ICI in our institution between January 2016 and January 2020. The cancer center is the highest volume cancer center and the only National Cancer Institute designated cancer center in the state of Kentucky. The institutional review board approved the study. Demographics, treatment plans, and outcomes were obtained by reviewing electronic health records and Kentucky Cancer Registry (KCR). US Food and Drug administration approved next‐generation sequencing (NGS) platforms‐ FoundationOne® CDx and FoundationOne® Dx panels were used for mutational analysis of tumor samples. These tests can be used to detect substitutions, insertions, deletions, and copy number alterations in 324 genes and selected gene rearrangements. The system also estimates tumor mutational burden and microsatellite instability (MSI) using DNA isolated from tumor tissue specimens. MSI status is determined by a genome‐wide analysis of 95 microsatellite loci. PDL1 expression is tested using PD‐L1 22C3 IHC with interpretation using Tumor Proportion Score (TPS). Tumor mutational burden (TMB) is reported as mutations per megabase (mut/Mb) unit. It is further subdivided into high (≥20Muts/Mb), intermediate (6–19 Muts/Mb), and low (≤5Muts/Mb). Patients with indeterminate TMB were excluded from the analysis. For analysis, TMB was dichotomized as high and low to intermediate. Only genomic alterations of known significance were included in the analysis. One investigator assessed radiologic response to ICI therapy for all patients using Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 by analyzing radiology reports and image records. Response categories were divided into complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD). 146 patients who did not have complete molecular and radiological information or lost to follow up before complete evaluation were excluded from the analysis. Progression‐free survival (PFS), radiological response, and autoimmune side effects were analyzed with various molecular biomarkers.
2.1 Statistical analysis
Categorical variables were analyzed as percentages and continuous variables as means or medians. Statistical analysis was performed using SPSS 26.0 and JMP 14 software. Logistic regression, Fisher's exact test, Kaplan‐Meier method, log‐rank test, and Cox regression were used to analyze clinical features and efficacy outcomes. p‐value <0.05 was considered to be statistically significant. Overall survival was not considered for analysis as there were only eight deaths, probably due to a shorter period of follow‐up.
3 RESULTS
3.1 Patient characteristics
Sixty nine patients had genomic and radiologic data for inclusion in the study. The median follow‐up period was 63 weeks. 36 (52.2%) subjects were male. The mean age of the study population was 62 (range: 27–95 years), and 14.5% were over 75 years of age. 91.3% were of Caucasian ethnicity. There was a very high prevalence of smoking (78.3%), and 66.7% of the never‐smokers also had recorded secondhand smoke exposure. 13% of the study population also used e‐cigarettes. 100% of patients with NSCLC were smokers. 45% of patients were from Appalachian region and 60% from rural counties. NSCLC constituted the majority (37.7%) of the tumor types included in the study, followed by squamous cell cancer (SCC) of the head and neck and melanoma. 23% of the patients had brain metastasis at diagnosis or on progression. 100% of patients with NSCLC were smokers (Table 1).
TABLE 1 Baseline characteristics of the study population
Characteristics Total (%)
Age group
18–64 40 (58)
65–74 19 (27.5)
≥ 75 10 (14.5)
Male: Female 36 (52.2): 33 (47.8)
Race
Caucasian 63 (91.3)
African American 4 (5.8)
Hispanic 1 (1.4)
Asian 1 (1.4)
Cancer Site
NSCLC 26 (37.7)
SCC Head & Neck 8 (11.6)
Melanoma 7 (10.1)
Gastrointestinal 7 (10.1)
Kidney/Bladder 6 (8.6)
Small Cell lung Cancer 5 (7.2)
Hepatobiliary 2 (2.9)
Breast 2 (2.9)
Ovary and uterus 2 (2.9)
Thyroid 2 (2.9)
Merkel Cell 1 (1.4)
Unknown primary 1 (1.4)
Tobacco use
Current/previous use 54 (78.3)
Never used 15 (21.7)
Secondhand exposure 10 (14.5)
Abbreviations: NSCLC, Non‐small cell lung cancer; SCC, Squamous cell carcinoma.
John Wiley & Sons, Ltd
3.2 Treatment
Mean time to ICI use from diagnosis was 69.5 weeks. Pembrolizumab was the most commonly used ICI (65%) followed by nivolumab and ipilimumab (16% each), and most patients received single‐agent immunotherapy (77%). 40 patients (58%) received ICI treatment as first line therapy, 23 (33.3%) as second line and 6 (8.9%) received as third line for FDA‐approved indications. None of the patients received ICI for high‐TMB or MSI‐H status. About half of these patients (47.8%) had iRAEs with grade 3/4 adverse events reported at 14.4%. Hyperprogression, which is treatment failure within two months of treatment initiation or ≥50% increase in tumor burden in 2 diameters or ≥100% in one diameter, was present in six patients (8.7%). Radiologic pseudo‐progression was found only in 2 patients, one with NSCLC and one with squamous cell cancer of head and neck (Table 2).
TABLE 2 Treatment and biomarker characteristics of study population
Characteristics n (%)
ICI
Atezolizumab 2 (2.9)
Ipilimumab‐Nivolumab 11 (15.9)
Nivolumab 11 (15.9)
Pembrolizumab 45 (65.2)
IRAEs
Any 33 (47.8)
Grade 1 7 (10.1)
Grade 2 16 (23.2)
Grade 3/4 10 (14.4)
Tumor Mutational Burden
≥20 mut/Mb 9 (13)
6–19 mut/Mb 32 (46.4)
≤ 5 mut/Mb 28 (40.6)
PDL1 tumor proportion score
0 18 (26.1)
1–49% 28 (40.6)
≥50 17 (24.6)
Not able to assess 6 (8.7)
Microsatellite stability
Stable 61 (88.4)
Unstable 6 (8.7)
Unknown 2 (2.9)
Best Response
CR 14 (20.3)
PR 22 (31.9)
SD 12 (17.4)
PD 21 (30.4)
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3.3 Biomarkers and Mutational assay
The majority of the tumor samples (65.2%) had a positive PDL‐1 expression represented as a tumor proportion score (TPS) ≥1%. 90% of the tumors were microsatellite stable, and the average TMB was 12.6 (range 0–117). 13% of patients had TMB ≥20 mut/Mb and 46.4% tumors had TMB between 6–19 mut/Mb. The NGS panel detected TP53 as the most common (62.3%) tumor mutation. It was followed by CDKN1B/2A (40.5%), NOTCH (33.3%), and PIK3CA/2B (33.3%) mutations. STK11 mutation was found in 16% of patients. TMB did not correlate to smoking status or pack years (Table 2, Figure 1, Figure 2).
FIGURE 1 Percentage of patients with mutations in cBioPortal and this study. (A) NSCLC cohort in both studies with genomic alterations associated with smoking. (B) Genomic alterations involving PIK3/AKT/mTOR pathway. (C) Alterations implicated in homologous recombinant repair. (CBP: cBioPortal)
FIGURE 2 Mutational analysis of patients receiving immunotherapy grouped based on radiologic response, in the order of mutational load and frequency of mutations
Tumor mutations commonly associated with smoking (BRAF, JAK2, JAK3, NOTCH1, TP53) were higher in the study population compared to cBioPortal database metastatic solid tumor cohorts. 14 , 15 There was similar difference on evaluation of genomic alterations involving PIK3/AKT/mTOR pathway and alterations implicated in homologous recombinant repair. BRCA1, MTOR, and PTEN mutations were, however, less common in the study group compared to the trial cohort.
3.4 Response and outcome by PDL1 expression and TMB
TMB was not associated with smoking status or pack years. Patients with high TMB (≥20 mut/Mb) had an overall radiologic response rate (CR+PR) of 55.6% compared to 51.7% in low‐intermediate TMB group (p = 0.83). Median PFS was higher in high TMB compared to the low‐intermediate group and the results reached statistical significance (median not reached vs. 26 weeks; HR=0.37. 95%CI 0.13, 1.05). Although there was improvement in PFS (median 53 vs. 26 weeks, HR=1, 95%CI 0.37, 2.72) this was not statistically significant when the FDA‐approved cut off of ≥10mut/Mb for ICI use was used to identify high TMB. Radiologic responders were identical in both groups. (0.52% vs. 0.52%, OR = 1, p = 1). PDL1 expression was not associated with radiologic response, but there was a trend toward improved PFS in patients with tumors expressing PDL1 (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). There was no significant correlation between size change of the target lesion with ICI therapy and absolute TMB values (R2 = 0.023) (Figure 3, Table 3).
FIGURE 3 Kaplan‐Meier graphs depicting progression‐free survival in patients based on tumor samples showing (A) High TMB and low/intermediate TMB; (B) PDL1 expression; (C) Presence of IRAEs; (D) Presence of PIK3 mutation; (E) Presence of FGFR mutation; (F) Presence of BRAF mutation
TABLE 3 Table showing ORR based on various factors with odds ratio calculated using logistic regression model
Variable Total Responders (CR/PR) n (%) Non‐responders (SD/PD) n (%) Overall response rate OR 95% CI
All patients 69 36 (52.2) 33 (47.8) 52.2%
Age <65 40 19 (47.5) 21 (52.5) 47.5% 0.64 (0.24–1.68)
Age >65 29 17 (58.6) 12 (41.4) 58.6%
Male 36 16 (44.4) 20 (55.6) 44.4% 1.92 (0.74–5.02)
Female 33 20 (60.6) 13 (39.4) 60.6%
Smoker 54 26 (48.1) 28 (51.9) 48.1% 2.15 (0.64–7.14)
Non‐smoker 15 10 (66.7) 5 (33.1) 66.7%
IRAE present 34 19 (55.9) 15 (44.1) 55.9% 0.75 (0.29–1.92)
IRAE absent 35 17 (48.6) 18 (51.4) 48.6%
High TMB 9 5 (55.6) 4 (44.4) 55.6% 1.17 (0.29–4.78)
Low/int TMB 60 31 (51.7) 29 (48.3) 51.7%
TMB <10 46 24 (52.2) 22 (47.8) 52.2% 1.00 (0.36–2.72)
TMB ≥10 23 12 (52.2) 11 (47.8) 52.2%
PDL1 0% 18 6 (33.3) 12 (64.7) 33.3% 0.45 (0.12–1.68)
PDL1 >1% 45 25 (55.6) 20 (44.4) 55.6%
PIK3 mutated 23 16 (69.6) 7 (30.4) 69.6% 0.34 (0.12–0.97)
PIK3 wild type 46 20 (43.5) 26 (56.5) 43.5%
FGFR mutated 16 13 (72.2) 5 (27.8) 72.2% 0.32 (0.98–1.01)
FGFR wild type 51 23 (45.1) 28 (54.9) 45.1%
ROS1 mutated 10 9 (90.0) 1 (10.0) 90.0% 0.09 (0.01–0.79)
ROS1 wild type 59 27 (45.8) 32 (54.2) 45.8%
BRAF mutated 5 3 (60.0) 2 (40.0) 60.0% 0.71 (0.11–4.54)
BRAF wild type 64 33 (51.6) 31 (48.4) 51.6%
STK 11 mutation 11 4 (36.4) 7 (63.6) 36.4% 2.15 (0.57–8.17)
STK11 wild type 58 32 (55.2) 26 (44.8) 55.2%
Bold indicates statistically significant values.
John Wiley & Sons, Ltd
3.5 Response and outcome by tumor mutations
The presence of BRAF mutation conferred shorter PFS with immunotherapy (median 17 vs. 39 weeks. HR = 0.35. 95%CI 0.14, 0.91) but had no significant association with radiologic response. STK11 mutation did not have a significant impact on PFS (median 30 vs. 39 weeks, HR=0.88. 95%CI 0.39, 2.0) or radiologic response (OR = 1.61, p = 0.58). Presence of KRAS mutations also did not show significant impact on PFS (median 48 vs. 38 weeks, HR=1.27, 95%CI 0.62, 2.58) or radiologic response (OR = 1.12, p = 0.84) (Figure 3, Table 3).
Statistically significant improvement in PFS was observed in the PIK3 mutated (PIK3CA/PIK3C2B) group (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). (Figure 3) This was independent of TMB status or PDL1 expression status (HR 3.24, p = 0.016). Patients with PIK3 mutations had a higher overall response rate (ORR) than the unmutated group (69.6% vs. 43.5%, OR 0.34; p = 0.045). PIK3 mutated patients also had a higher risk of developing IRAEs (73.9% vs. 37%, OR = 0.21 p = 0.005), but the presence of mutation did not associate with TMB, PDL1 expression or microsatellite stability status ruling out collinearity.
There was a difference in ORR with FGFR mutations (72.2% vs 45.1%, OR 0.32; p = 0.05) and ROS1 mutation (90% vs. 45.8%, OR 0.09; p = 0.029). With FGFR mutation, there was a trend toward statistical significance for PFS with immunotherapy (median 39 vs. 30 weeks. HR = 1.84. 95%CI 0.90, 3.76), which was not seen with ROS1 mutation.
3.6 Response and outcome (others)
There was no statistically significant difference in radiologic response and PFS with ICI therapy based on smoking status, ICI drug, MSS status, incidence of IRAEs, or age (below and above 65 years of age).
4 DISCUSSION
Our study was aimed at evaluating clinicopathologic characteristics and outcomes in a subset of population with the highest incidence of cancer in the country and often underrepresented in clinical trials. The outcomes with immunotherapy, incidence of iRAEs and biomarker profiling of these patients are poorly understood. With the current data available only from a carefully selected clinical trial population, many biomarkers that could be effective in such selected population might have been overlooked. The study also looked at potential markers of immunotherapy response in this patient population (90).
The prevalence of smoking and secondhand smoke exposure was high in the study group. The study did not find association of smoking status with TMB. Nearly half (47.8%) of the patients experienced any degree of IRAEs. The median tumor mutation burden was 12.6 mutations/Mb which was at least twofold to fourfold compared to other similar studies. 16 , 17 Our results show the prevalence of PDL1 expression, TMB in our study group are similar to ones seen in previous clinical trials. Compared to historic cohorts, the prevalence of PIK3/AKT/mTOR pathway and homologous recombinant repair alterations were higher in the study group. Smoking associated tumor genomic alterations was also significantly higher compared to similar cohorts.
High‐tumor mutational burden, and the presence of PIK3 mutation conferred better progression‐free survival with immunotherapy across cancer types. This PFS benefit seen in PIK3 mutated patients was independent of PDL1 status or TMB. The effect of PDL1 expression and FGFR mutation on PFS trended toward statistical significance. The presence of PIK3 mutation and ROS1 mutation also had a statistically significant favorable impact on the best overall radiologic tumor response while with FGFR mutation, this trended toward statistical significance. The high incidence of IRAEs in the PIK3 mutated group also points toward possible increased PDL1 inhibitor activity. STK11 mutation, which was previously implicated in immunotherapy resistance, did not significantly affect immunotherapy response or outcomes. Although the absolute numbers were small, patients with BRAF mutations had a poor outcome with immune therapy.
The PIK3/AKT/mTOR (PAM) pathway is considered a master regulator of cancer and plays a vital role in tumor growth, proliferation, angiogenesis, and cell survival. 18 PIK3CA is the most studied among PIK3 mutations, with amplification or clustering of somatic mutations occurring in up to 30% of endometrial, breast, ovarian, and colon cancers while PIK3CB is found in thyroid and lung cancers. 19 PI3KCA/CB mutations are primarily activating, while the pathway inhibiting PIK3R1 mutations are mostly inactivating. 20 These mutations were also implicated in chemotherapy and HER2 blocker resistance. 21 , 22 The pathway, more importantly, plays a stimulatory role in PDL1 transcription and expression on tumor cells. 23 , 24 Despite the abundance of laboratory and animal data, clinical data linking various PIK3 protein mutations and immunotherapy responses are lacking.
The study has limitations with small sample size, short follow‐up period and being a single‐center study. Most of the patients who received ICI at the institution were not included in the final analysis due to incomplete data or loss to follow up making the need of prospective trials important. The results should prompt further evaluation of these potential biomarkers and more widespread real‐world data publications.
5 CONCLUSION
The study characterizes the ICI response, IRAEs, and mutational profile in a population with high prevalence of smoking and the highest cancer incidence and mortality in the country. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway were higher in the study group compared to similar cohorts. The previously reported positive evidence for TMB and PDL1 expression as ICI biomarkers were replicated in this study. The presence of PIK3 mutation conferred better progression‐free survival and radiologic response with immunotherapy across cancer types. Although conflicting evidence exists on using these markers across cancers for patient selection, these could still be relevant in specific target populations with significant risk factors like smoking in our population. More extensive studies and long‐term follow‐up data are needed to confirm the clinical validity and role of individual mutations in immunotherapy response. Furthermore, more real‐world data is needed to help identify specific biomarkers based on population and risk factors.
CONFLICTS OF INTEREST
Authors Aasems Jacob, Jianrong Wu, Jill Kolesar, Eric Durbin, Aju Mathew and Susanne Arnold express no conflicts of interest. Aman Chauhan has received research grant from BMS, Clovis, Lexicon; Advisor Lexicon, Ipsen.
ETHICAL APPROVAL AND INFORMED CONSENT
University of Kentucky Institutional Review Board approved the study (IRB# #49450 on 8/9/2019)
The Office of Research Integrity under IRB, University of Kentucky authorized waiver of informed consent as the study involved no more than minimal risks for the subjects and their privacy.
DATA AVAILABILITY STATEMENT
Raw data were generated at University of Kentucky and Kentucky Cancer Registry. Derived data supporting the findings of this study are available from the corresponding author AJ on request. | ATEZOLIZUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33619913 | 19,777,723 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Real world clinicopathologic observations of patients with metastatic solid tumors receiving immune checkpoint inhibitor therapy: Analysis from Kentucky Cancer Registry.
The state of Kentucky has the highest cancer incidence and mortality in the United States. High-risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution. Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure was 78.3% and 14.5%, respectively. TP53 (62.3%), CDKN1B/2A (40.5%), NOTCH and PIK3 (33.3%) were the most common alterations in tumors. 67.4% were PDL1 positive and 59.4% had intermediate-high tumor mutational burden (TMB). Median TMB (12.6) was twofold to fourfold compared to clinical trials. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway mutations was higher compared to historic cohorts. PDL1 expression had no significant effect on radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended toward statistical significance (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). Median PFS was higher in the high-TMB cohort compared to low-intermediate TMB (median not reached vs. 26 weeks; HR = 0.37. 95%CI 0.13, 1.05). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). This was independent of tumor mutational burden (TMB) status or PDL1 expression status. PIK3 mutants had a higher overall response rate than the wild type (69.6% vs. 43.5%, OR 0.34; p = 0.045). The results should prompt further evaluation of these potential biomarkers and more widespread real-world data publications which might help determine biomarkers that could benefit specific populations.
1 BACKGROUND
Kentucky has the highest cancer incidence and mortality rates in the country with mortality rates nearly 50% higher than the national average. 1 Although this has been mainly attributed to the high‐smoking prevalence in the state, economic, and health care disparities, and genetic factors also play a key role. High‐risk populations such as this are often underrepresented in clinical trials. This could be the reason behind variation of smoking status, predictive biomarkers and tumor genomic alteration between real‐world and clinical trials. 2
Immune checkpoint inhibitors (ICI) were developed to counter the upregulation of immune checkpoints by tumors by targeting programmed cell death protein (PD‐1)/programmed death‐ligand 1 (PDL‐1) or common T lymphocyte antigen‐4 (CTLA‐4), resulting in recognition and killing of tumor cells by the host immune system. There are over two dozen FDA‐approved indications for this class of drugs currently, and they are being increasingly studied in various clinical trials, gradually broadening indications. With accumulating data, it has become clear that the treatment benefits are not homogenous among all the patients. Response rates to single‐agent PD‐1/PDL‐1 inhibitors are variable with 40% in melanoma, 25% in non‐small cell lung cancer (NSCLC), and 19% in renal cell carcinoma. 3 , 4 , 5 , 6 , 7 This highlights the importance of finding a discriminating biomarker that could predict the outcomes of ICI therapy. PDL1 expression, microsatellite instability status, tumor mutation burden, CD8+ T cell infiltration are some of the extensively studied predictive biomarkers; however, with conflicting data in different studies. 8 , 9 The variation in patient selection criteria, assays and determinants used to assess PDL1 expression could have contributed to this discrepancy. 10 Immune‐related adverse events (iRAEs) from ICI therapy affect patients differently, and it is critical to understand its determinants. Evaluation of the current conflicting data on the association between the incidence of iRAEs and response to ICI is equally essential. 11 , 12 Most importantly, there is a lack of real‐world data on response to ICI response and patient outcomes in diverse populations. Real‐world datasets, which reveal genomic profiling and clinical outcomes, provide an important tool to recognize inferences on biomarkers of response and resistance. These data could also enable the discovery of novel biomarkers not be seen in the highly selective clinical trials. Randomized controlled trials with strict entry requirements to guarantee internal stability can lead to the loss of external scalability. This could be due to the exclusion of patients with poor prognosis, older patients, patients with brain metastases, and an ECOG score of 2 or more. Mutational analyses have now enabled subclassification of tumors into molecularly defined subtypes. Evaluation of ICI response and resistance in tumors that demonstrate these mutations is a muddy landscape with little valuable data.
Our study aims to assess various molecular markers and their impact on progression‐free survival and radiological response rates with ICI therapy. This assessment is especially important in our population as Kentucky has an exceedingly high‐smoking prevalence of 24.6% among adults and has the highest incidence of cancer in the United States. This population could present a varied biomarker profile and responses compared to that seen in clinical trials and provide insight into new biomarkers. In recent studies, a higher tumor mutational burden was identified among patients who smoke, with the possibility of smoking‐specific mutations as drivers for oncogenesis. 13 Although the results might not be generalizable, they can give potential information to further search for biomarkers and help identify specific signatures in this high‐risk population.
2 METHODOLOGY
We conducted a retrospective analysis of all patients with metastatic solid tumors above 18 years of age who received ICI in our institution between January 2016 and January 2020. The cancer center is the highest volume cancer center and the only National Cancer Institute designated cancer center in the state of Kentucky. The institutional review board approved the study. Demographics, treatment plans, and outcomes were obtained by reviewing electronic health records and Kentucky Cancer Registry (KCR). US Food and Drug administration approved next‐generation sequencing (NGS) platforms‐ FoundationOne® CDx and FoundationOne® Dx panels were used for mutational analysis of tumor samples. These tests can be used to detect substitutions, insertions, deletions, and copy number alterations in 324 genes and selected gene rearrangements. The system also estimates tumor mutational burden and microsatellite instability (MSI) using DNA isolated from tumor tissue specimens. MSI status is determined by a genome‐wide analysis of 95 microsatellite loci. PDL1 expression is tested using PD‐L1 22C3 IHC with interpretation using Tumor Proportion Score (TPS). Tumor mutational burden (TMB) is reported as mutations per megabase (mut/Mb) unit. It is further subdivided into high (≥20Muts/Mb), intermediate (6–19 Muts/Mb), and low (≤5Muts/Mb). Patients with indeterminate TMB were excluded from the analysis. For analysis, TMB was dichotomized as high and low to intermediate. Only genomic alterations of known significance were included in the analysis. One investigator assessed radiologic response to ICI therapy for all patients using Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 by analyzing radiology reports and image records. Response categories were divided into complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD). 146 patients who did not have complete molecular and radiological information or lost to follow up before complete evaluation were excluded from the analysis. Progression‐free survival (PFS), radiological response, and autoimmune side effects were analyzed with various molecular biomarkers.
2.1 Statistical analysis
Categorical variables were analyzed as percentages and continuous variables as means or medians. Statistical analysis was performed using SPSS 26.0 and JMP 14 software. Logistic regression, Fisher's exact test, Kaplan‐Meier method, log‐rank test, and Cox regression were used to analyze clinical features and efficacy outcomes. p‐value <0.05 was considered to be statistically significant. Overall survival was not considered for analysis as there were only eight deaths, probably due to a shorter period of follow‐up.
3 RESULTS
3.1 Patient characteristics
Sixty nine patients had genomic and radiologic data for inclusion in the study. The median follow‐up period was 63 weeks. 36 (52.2%) subjects were male. The mean age of the study population was 62 (range: 27–95 years), and 14.5% were over 75 years of age. 91.3% were of Caucasian ethnicity. There was a very high prevalence of smoking (78.3%), and 66.7% of the never‐smokers also had recorded secondhand smoke exposure. 13% of the study population also used e‐cigarettes. 100% of patients with NSCLC were smokers. 45% of patients were from Appalachian region and 60% from rural counties. NSCLC constituted the majority (37.7%) of the tumor types included in the study, followed by squamous cell cancer (SCC) of the head and neck and melanoma. 23% of the patients had brain metastasis at diagnosis or on progression. 100% of patients with NSCLC were smokers (Table 1).
TABLE 1 Baseline characteristics of the study population
Characteristics Total (%)
Age group
18–64 40 (58)
65–74 19 (27.5)
≥ 75 10 (14.5)
Male: Female 36 (52.2): 33 (47.8)
Race
Caucasian 63 (91.3)
African American 4 (5.8)
Hispanic 1 (1.4)
Asian 1 (1.4)
Cancer Site
NSCLC 26 (37.7)
SCC Head & Neck 8 (11.6)
Melanoma 7 (10.1)
Gastrointestinal 7 (10.1)
Kidney/Bladder 6 (8.6)
Small Cell lung Cancer 5 (7.2)
Hepatobiliary 2 (2.9)
Breast 2 (2.9)
Ovary and uterus 2 (2.9)
Thyroid 2 (2.9)
Merkel Cell 1 (1.4)
Unknown primary 1 (1.4)
Tobacco use
Current/previous use 54 (78.3)
Never used 15 (21.7)
Secondhand exposure 10 (14.5)
Abbreviations: NSCLC, Non‐small cell lung cancer; SCC, Squamous cell carcinoma.
John Wiley & Sons, Ltd
3.2 Treatment
Mean time to ICI use from diagnosis was 69.5 weeks. Pembrolizumab was the most commonly used ICI (65%) followed by nivolumab and ipilimumab (16% each), and most patients received single‐agent immunotherapy (77%). 40 patients (58%) received ICI treatment as first line therapy, 23 (33.3%) as second line and 6 (8.9%) received as third line for FDA‐approved indications. None of the patients received ICI for high‐TMB or MSI‐H status. About half of these patients (47.8%) had iRAEs with grade 3/4 adverse events reported at 14.4%. Hyperprogression, which is treatment failure within two months of treatment initiation or ≥50% increase in tumor burden in 2 diameters or ≥100% in one diameter, was present in six patients (8.7%). Radiologic pseudo‐progression was found only in 2 patients, one with NSCLC and one with squamous cell cancer of head and neck (Table 2).
TABLE 2 Treatment and biomarker characteristics of study population
Characteristics n (%)
ICI
Atezolizumab 2 (2.9)
Ipilimumab‐Nivolumab 11 (15.9)
Nivolumab 11 (15.9)
Pembrolizumab 45 (65.2)
IRAEs
Any 33 (47.8)
Grade 1 7 (10.1)
Grade 2 16 (23.2)
Grade 3/4 10 (14.4)
Tumor Mutational Burden
≥20 mut/Mb 9 (13)
6–19 mut/Mb 32 (46.4)
≤ 5 mut/Mb 28 (40.6)
PDL1 tumor proportion score
0 18 (26.1)
1–49% 28 (40.6)
≥50 17 (24.6)
Not able to assess 6 (8.7)
Microsatellite stability
Stable 61 (88.4)
Unstable 6 (8.7)
Unknown 2 (2.9)
Best Response
CR 14 (20.3)
PR 22 (31.9)
SD 12 (17.4)
PD 21 (30.4)
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3.3 Biomarkers and Mutational assay
The majority of the tumor samples (65.2%) had a positive PDL‐1 expression represented as a tumor proportion score (TPS) ≥1%. 90% of the tumors were microsatellite stable, and the average TMB was 12.6 (range 0–117). 13% of patients had TMB ≥20 mut/Mb and 46.4% tumors had TMB between 6–19 mut/Mb. The NGS panel detected TP53 as the most common (62.3%) tumor mutation. It was followed by CDKN1B/2A (40.5%), NOTCH (33.3%), and PIK3CA/2B (33.3%) mutations. STK11 mutation was found in 16% of patients. TMB did not correlate to smoking status or pack years (Table 2, Figure 1, Figure 2).
FIGURE 1 Percentage of patients with mutations in cBioPortal and this study. (A) NSCLC cohort in both studies with genomic alterations associated with smoking. (B) Genomic alterations involving PIK3/AKT/mTOR pathway. (C) Alterations implicated in homologous recombinant repair. (CBP: cBioPortal)
FIGURE 2 Mutational analysis of patients receiving immunotherapy grouped based on radiologic response, in the order of mutational load and frequency of mutations
Tumor mutations commonly associated with smoking (BRAF, JAK2, JAK3, NOTCH1, TP53) were higher in the study population compared to cBioPortal database metastatic solid tumor cohorts. 14 , 15 There was similar difference on evaluation of genomic alterations involving PIK3/AKT/mTOR pathway and alterations implicated in homologous recombinant repair. BRCA1, MTOR, and PTEN mutations were, however, less common in the study group compared to the trial cohort.
3.4 Response and outcome by PDL1 expression and TMB
TMB was not associated with smoking status or pack years. Patients with high TMB (≥20 mut/Mb) had an overall radiologic response rate (CR+PR) of 55.6% compared to 51.7% in low‐intermediate TMB group (p = 0.83). Median PFS was higher in high TMB compared to the low‐intermediate group and the results reached statistical significance (median not reached vs. 26 weeks; HR=0.37. 95%CI 0.13, 1.05). Although there was improvement in PFS (median 53 vs. 26 weeks, HR=1, 95%CI 0.37, 2.72) this was not statistically significant when the FDA‐approved cut off of ≥10mut/Mb for ICI use was used to identify high TMB. Radiologic responders were identical in both groups. (0.52% vs. 0.52%, OR = 1, p = 1). PDL1 expression was not associated with radiologic response, but there was a trend toward improved PFS in patients with tumors expressing PDL1 (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). There was no significant correlation between size change of the target lesion with ICI therapy and absolute TMB values (R2 = 0.023) (Figure 3, Table 3).
FIGURE 3 Kaplan‐Meier graphs depicting progression‐free survival in patients based on tumor samples showing (A) High TMB and low/intermediate TMB; (B) PDL1 expression; (C) Presence of IRAEs; (D) Presence of PIK3 mutation; (E) Presence of FGFR mutation; (F) Presence of BRAF mutation
TABLE 3 Table showing ORR based on various factors with odds ratio calculated using logistic regression model
Variable Total Responders (CR/PR) n (%) Non‐responders (SD/PD) n (%) Overall response rate OR 95% CI
All patients 69 36 (52.2) 33 (47.8) 52.2%
Age <65 40 19 (47.5) 21 (52.5) 47.5% 0.64 (0.24–1.68)
Age >65 29 17 (58.6) 12 (41.4) 58.6%
Male 36 16 (44.4) 20 (55.6) 44.4% 1.92 (0.74–5.02)
Female 33 20 (60.6) 13 (39.4) 60.6%
Smoker 54 26 (48.1) 28 (51.9) 48.1% 2.15 (0.64–7.14)
Non‐smoker 15 10 (66.7) 5 (33.1) 66.7%
IRAE present 34 19 (55.9) 15 (44.1) 55.9% 0.75 (0.29–1.92)
IRAE absent 35 17 (48.6) 18 (51.4) 48.6%
High TMB 9 5 (55.6) 4 (44.4) 55.6% 1.17 (0.29–4.78)
Low/int TMB 60 31 (51.7) 29 (48.3) 51.7%
TMB <10 46 24 (52.2) 22 (47.8) 52.2% 1.00 (0.36–2.72)
TMB ≥10 23 12 (52.2) 11 (47.8) 52.2%
PDL1 0% 18 6 (33.3) 12 (64.7) 33.3% 0.45 (0.12–1.68)
PDL1 >1% 45 25 (55.6) 20 (44.4) 55.6%
PIK3 mutated 23 16 (69.6) 7 (30.4) 69.6% 0.34 (0.12–0.97)
PIK3 wild type 46 20 (43.5) 26 (56.5) 43.5%
FGFR mutated 16 13 (72.2) 5 (27.8) 72.2% 0.32 (0.98–1.01)
FGFR wild type 51 23 (45.1) 28 (54.9) 45.1%
ROS1 mutated 10 9 (90.0) 1 (10.0) 90.0% 0.09 (0.01–0.79)
ROS1 wild type 59 27 (45.8) 32 (54.2) 45.8%
BRAF mutated 5 3 (60.0) 2 (40.0) 60.0% 0.71 (0.11–4.54)
BRAF wild type 64 33 (51.6) 31 (48.4) 51.6%
STK 11 mutation 11 4 (36.4) 7 (63.6) 36.4% 2.15 (0.57–8.17)
STK11 wild type 58 32 (55.2) 26 (44.8) 55.2%
Bold indicates statistically significant values.
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3.5 Response and outcome by tumor mutations
The presence of BRAF mutation conferred shorter PFS with immunotherapy (median 17 vs. 39 weeks. HR = 0.35. 95%CI 0.14, 0.91) but had no significant association with radiologic response. STK11 mutation did not have a significant impact on PFS (median 30 vs. 39 weeks, HR=0.88. 95%CI 0.39, 2.0) or radiologic response (OR = 1.61, p = 0.58). Presence of KRAS mutations also did not show significant impact on PFS (median 48 vs. 38 weeks, HR=1.27, 95%CI 0.62, 2.58) or radiologic response (OR = 1.12, p = 0.84) (Figure 3, Table 3).
Statistically significant improvement in PFS was observed in the PIK3 mutated (PIK3CA/PIK3C2B) group (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). (Figure 3) This was independent of TMB status or PDL1 expression status (HR 3.24, p = 0.016). Patients with PIK3 mutations had a higher overall response rate (ORR) than the unmutated group (69.6% vs. 43.5%, OR 0.34; p = 0.045). PIK3 mutated patients also had a higher risk of developing IRAEs (73.9% vs. 37%, OR = 0.21 p = 0.005), but the presence of mutation did not associate with TMB, PDL1 expression or microsatellite stability status ruling out collinearity.
There was a difference in ORR with FGFR mutations (72.2% vs 45.1%, OR 0.32; p = 0.05) and ROS1 mutation (90% vs. 45.8%, OR 0.09; p = 0.029). With FGFR mutation, there was a trend toward statistical significance for PFS with immunotherapy (median 39 vs. 30 weeks. HR = 1.84. 95%CI 0.90, 3.76), which was not seen with ROS1 mutation.
3.6 Response and outcome (others)
There was no statistically significant difference in radiologic response and PFS with ICI therapy based on smoking status, ICI drug, MSS status, incidence of IRAEs, or age (below and above 65 years of age).
4 DISCUSSION
Our study was aimed at evaluating clinicopathologic characteristics and outcomes in a subset of population with the highest incidence of cancer in the country and often underrepresented in clinical trials. The outcomes with immunotherapy, incidence of iRAEs and biomarker profiling of these patients are poorly understood. With the current data available only from a carefully selected clinical trial population, many biomarkers that could be effective in such selected population might have been overlooked. The study also looked at potential markers of immunotherapy response in this patient population (90).
The prevalence of smoking and secondhand smoke exposure was high in the study group. The study did not find association of smoking status with TMB. Nearly half (47.8%) of the patients experienced any degree of IRAEs. The median tumor mutation burden was 12.6 mutations/Mb which was at least twofold to fourfold compared to other similar studies. 16 , 17 Our results show the prevalence of PDL1 expression, TMB in our study group are similar to ones seen in previous clinical trials. Compared to historic cohorts, the prevalence of PIK3/AKT/mTOR pathway and homologous recombinant repair alterations were higher in the study group. Smoking associated tumor genomic alterations was also significantly higher compared to similar cohorts.
High‐tumor mutational burden, and the presence of PIK3 mutation conferred better progression‐free survival with immunotherapy across cancer types. This PFS benefit seen in PIK3 mutated patients was independent of PDL1 status or TMB. The effect of PDL1 expression and FGFR mutation on PFS trended toward statistical significance. The presence of PIK3 mutation and ROS1 mutation also had a statistically significant favorable impact on the best overall radiologic tumor response while with FGFR mutation, this trended toward statistical significance. The high incidence of IRAEs in the PIK3 mutated group also points toward possible increased PDL1 inhibitor activity. STK11 mutation, which was previously implicated in immunotherapy resistance, did not significantly affect immunotherapy response or outcomes. Although the absolute numbers were small, patients with BRAF mutations had a poor outcome with immune therapy.
The PIK3/AKT/mTOR (PAM) pathway is considered a master regulator of cancer and plays a vital role in tumor growth, proliferation, angiogenesis, and cell survival. 18 PIK3CA is the most studied among PIK3 mutations, with amplification or clustering of somatic mutations occurring in up to 30% of endometrial, breast, ovarian, and colon cancers while PIK3CB is found in thyroid and lung cancers. 19 PI3KCA/CB mutations are primarily activating, while the pathway inhibiting PIK3R1 mutations are mostly inactivating. 20 These mutations were also implicated in chemotherapy and HER2 blocker resistance. 21 , 22 The pathway, more importantly, plays a stimulatory role in PDL1 transcription and expression on tumor cells. 23 , 24 Despite the abundance of laboratory and animal data, clinical data linking various PIK3 protein mutations and immunotherapy responses are lacking.
The study has limitations with small sample size, short follow‐up period and being a single‐center study. Most of the patients who received ICI at the institution were not included in the final analysis due to incomplete data or loss to follow up making the need of prospective trials important. The results should prompt further evaluation of these potential biomarkers and more widespread real‐world data publications.
5 CONCLUSION
The study characterizes the ICI response, IRAEs, and mutational profile in a population with high prevalence of smoking and the highest cancer incidence and mortality in the country. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway were higher in the study group compared to similar cohorts. The previously reported positive evidence for TMB and PDL1 expression as ICI biomarkers were replicated in this study. The presence of PIK3 mutation conferred better progression‐free survival and radiologic response with immunotherapy across cancer types. Although conflicting evidence exists on using these markers across cancers for patient selection, these could still be relevant in specific target populations with significant risk factors like smoking in our population. More extensive studies and long‐term follow‐up data are needed to confirm the clinical validity and role of individual mutations in immunotherapy response. Furthermore, more real‐world data is needed to help identify specific biomarkers based on population and risk factors.
CONFLICTS OF INTEREST
Authors Aasems Jacob, Jianrong Wu, Jill Kolesar, Eric Durbin, Aju Mathew and Susanne Arnold express no conflicts of interest. Aman Chauhan has received research grant from BMS, Clovis, Lexicon; Advisor Lexicon, Ipsen.
ETHICAL APPROVAL AND INFORMED CONSENT
University of Kentucky Institutional Review Board approved the study (IRB# #49450 on 8/9/2019)
The Office of Research Integrity under IRB, University of Kentucky authorized waiver of informed consent as the study involved no more than minimal risks for the subjects and their privacy.
DATA AVAILABILITY STATEMENT
Raw data were generated at University of Kentucky and Kentucky Cancer Registry. Derived data supporting the findings of this study are available from the corresponding author AJ on request. | ATEZOLIZUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33619913 | 19,777,723 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Immune system disorder'. | Real world clinicopathologic observations of patients with metastatic solid tumors receiving immune checkpoint inhibitor therapy: Analysis from Kentucky Cancer Registry.
The state of Kentucky has the highest cancer incidence and mortality in the United States. High-risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution. Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure was 78.3% and 14.5%, respectively. TP53 (62.3%), CDKN1B/2A (40.5%), NOTCH and PIK3 (33.3%) were the most common alterations in tumors. 67.4% were PDL1 positive and 59.4% had intermediate-high tumor mutational burden (TMB). Median TMB (12.6) was twofold to fourfold compared to clinical trials. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway mutations was higher compared to historic cohorts. PDL1 expression had no significant effect on radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended toward statistical significance (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). Median PFS was higher in the high-TMB cohort compared to low-intermediate TMB (median not reached vs. 26 weeks; HR = 0.37. 95%CI 0.13, 1.05). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). This was independent of tumor mutational burden (TMB) status or PDL1 expression status. PIK3 mutants had a higher overall response rate than the wild type (69.6% vs. 43.5%, OR 0.34; p = 0.045). The results should prompt further evaluation of these potential biomarkers and more widespread real-world data publications which might help determine biomarkers that could benefit specific populations.
1 BACKGROUND
Kentucky has the highest cancer incidence and mortality rates in the country with mortality rates nearly 50% higher than the national average. 1 Although this has been mainly attributed to the high‐smoking prevalence in the state, economic, and health care disparities, and genetic factors also play a key role. High‐risk populations such as this are often underrepresented in clinical trials. This could be the reason behind variation of smoking status, predictive biomarkers and tumor genomic alteration between real‐world and clinical trials. 2
Immune checkpoint inhibitors (ICI) were developed to counter the upregulation of immune checkpoints by tumors by targeting programmed cell death protein (PD‐1)/programmed death‐ligand 1 (PDL‐1) or common T lymphocyte antigen‐4 (CTLA‐4), resulting in recognition and killing of tumor cells by the host immune system. There are over two dozen FDA‐approved indications for this class of drugs currently, and they are being increasingly studied in various clinical trials, gradually broadening indications. With accumulating data, it has become clear that the treatment benefits are not homogenous among all the patients. Response rates to single‐agent PD‐1/PDL‐1 inhibitors are variable with 40% in melanoma, 25% in non‐small cell lung cancer (NSCLC), and 19% in renal cell carcinoma. 3 , 4 , 5 , 6 , 7 This highlights the importance of finding a discriminating biomarker that could predict the outcomes of ICI therapy. PDL1 expression, microsatellite instability status, tumor mutation burden, CD8+ T cell infiltration are some of the extensively studied predictive biomarkers; however, with conflicting data in different studies. 8 , 9 The variation in patient selection criteria, assays and determinants used to assess PDL1 expression could have contributed to this discrepancy. 10 Immune‐related adverse events (iRAEs) from ICI therapy affect patients differently, and it is critical to understand its determinants. Evaluation of the current conflicting data on the association between the incidence of iRAEs and response to ICI is equally essential. 11 , 12 Most importantly, there is a lack of real‐world data on response to ICI response and patient outcomes in diverse populations. Real‐world datasets, which reveal genomic profiling and clinical outcomes, provide an important tool to recognize inferences on biomarkers of response and resistance. These data could also enable the discovery of novel biomarkers not be seen in the highly selective clinical trials. Randomized controlled trials with strict entry requirements to guarantee internal stability can lead to the loss of external scalability. This could be due to the exclusion of patients with poor prognosis, older patients, patients with brain metastases, and an ECOG score of 2 or more. Mutational analyses have now enabled subclassification of tumors into molecularly defined subtypes. Evaluation of ICI response and resistance in tumors that demonstrate these mutations is a muddy landscape with little valuable data.
Our study aims to assess various molecular markers and their impact on progression‐free survival and radiological response rates with ICI therapy. This assessment is especially important in our population as Kentucky has an exceedingly high‐smoking prevalence of 24.6% among adults and has the highest incidence of cancer in the United States. This population could present a varied biomarker profile and responses compared to that seen in clinical trials and provide insight into new biomarkers. In recent studies, a higher tumor mutational burden was identified among patients who smoke, with the possibility of smoking‐specific mutations as drivers for oncogenesis. 13 Although the results might not be generalizable, they can give potential information to further search for biomarkers and help identify specific signatures in this high‐risk population.
2 METHODOLOGY
We conducted a retrospective analysis of all patients with metastatic solid tumors above 18 years of age who received ICI in our institution between January 2016 and January 2020. The cancer center is the highest volume cancer center and the only National Cancer Institute designated cancer center in the state of Kentucky. The institutional review board approved the study. Demographics, treatment plans, and outcomes were obtained by reviewing electronic health records and Kentucky Cancer Registry (KCR). US Food and Drug administration approved next‐generation sequencing (NGS) platforms‐ FoundationOne® CDx and FoundationOne® Dx panels were used for mutational analysis of tumor samples. These tests can be used to detect substitutions, insertions, deletions, and copy number alterations in 324 genes and selected gene rearrangements. The system also estimates tumor mutational burden and microsatellite instability (MSI) using DNA isolated from tumor tissue specimens. MSI status is determined by a genome‐wide analysis of 95 microsatellite loci. PDL1 expression is tested using PD‐L1 22C3 IHC with interpretation using Tumor Proportion Score (TPS). Tumor mutational burden (TMB) is reported as mutations per megabase (mut/Mb) unit. It is further subdivided into high (≥20Muts/Mb), intermediate (6–19 Muts/Mb), and low (≤5Muts/Mb). Patients with indeterminate TMB were excluded from the analysis. For analysis, TMB was dichotomized as high and low to intermediate. Only genomic alterations of known significance were included in the analysis. One investigator assessed radiologic response to ICI therapy for all patients using Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 by analyzing radiology reports and image records. Response categories were divided into complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD). 146 patients who did not have complete molecular and radiological information or lost to follow up before complete evaluation were excluded from the analysis. Progression‐free survival (PFS), radiological response, and autoimmune side effects were analyzed with various molecular biomarkers.
2.1 Statistical analysis
Categorical variables were analyzed as percentages and continuous variables as means or medians. Statistical analysis was performed using SPSS 26.0 and JMP 14 software. Logistic regression, Fisher's exact test, Kaplan‐Meier method, log‐rank test, and Cox regression were used to analyze clinical features and efficacy outcomes. p‐value <0.05 was considered to be statistically significant. Overall survival was not considered for analysis as there were only eight deaths, probably due to a shorter period of follow‐up.
3 RESULTS
3.1 Patient characteristics
Sixty nine patients had genomic and radiologic data for inclusion in the study. The median follow‐up period was 63 weeks. 36 (52.2%) subjects were male. The mean age of the study population was 62 (range: 27–95 years), and 14.5% were over 75 years of age. 91.3% were of Caucasian ethnicity. There was a very high prevalence of smoking (78.3%), and 66.7% of the never‐smokers also had recorded secondhand smoke exposure. 13% of the study population also used e‐cigarettes. 100% of patients with NSCLC were smokers. 45% of patients were from Appalachian region and 60% from rural counties. NSCLC constituted the majority (37.7%) of the tumor types included in the study, followed by squamous cell cancer (SCC) of the head and neck and melanoma. 23% of the patients had brain metastasis at diagnosis or on progression. 100% of patients with NSCLC were smokers (Table 1).
TABLE 1 Baseline characteristics of the study population
Characteristics Total (%)
Age group
18–64 40 (58)
65–74 19 (27.5)
≥ 75 10 (14.5)
Male: Female 36 (52.2): 33 (47.8)
Race
Caucasian 63 (91.3)
African American 4 (5.8)
Hispanic 1 (1.4)
Asian 1 (1.4)
Cancer Site
NSCLC 26 (37.7)
SCC Head & Neck 8 (11.6)
Melanoma 7 (10.1)
Gastrointestinal 7 (10.1)
Kidney/Bladder 6 (8.6)
Small Cell lung Cancer 5 (7.2)
Hepatobiliary 2 (2.9)
Breast 2 (2.9)
Ovary and uterus 2 (2.9)
Thyroid 2 (2.9)
Merkel Cell 1 (1.4)
Unknown primary 1 (1.4)
Tobacco use
Current/previous use 54 (78.3)
Never used 15 (21.7)
Secondhand exposure 10 (14.5)
Abbreviations: NSCLC, Non‐small cell lung cancer; SCC, Squamous cell carcinoma.
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3.2 Treatment
Mean time to ICI use from diagnosis was 69.5 weeks. Pembrolizumab was the most commonly used ICI (65%) followed by nivolumab and ipilimumab (16% each), and most patients received single‐agent immunotherapy (77%). 40 patients (58%) received ICI treatment as first line therapy, 23 (33.3%) as second line and 6 (8.9%) received as third line for FDA‐approved indications. None of the patients received ICI for high‐TMB or MSI‐H status. About half of these patients (47.8%) had iRAEs with grade 3/4 adverse events reported at 14.4%. Hyperprogression, which is treatment failure within two months of treatment initiation or ≥50% increase in tumor burden in 2 diameters or ≥100% in one diameter, was present in six patients (8.7%). Radiologic pseudo‐progression was found only in 2 patients, one with NSCLC and one with squamous cell cancer of head and neck (Table 2).
TABLE 2 Treatment and biomarker characteristics of study population
Characteristics n (%)
ICI
Atezolizumab 2 (2.9)
Ipilimumab‐Nivolumab 11 (15.9)
Nivolumab 11 (15.9)
Pembrolizumab 45 (65.2)
IRAEs
Any 33 (47.8)
Grade 1 7 (10.1)
Grade 2 16 (23.2)
Grade 3/4 10 (14.4)
Tumor Mutational Burden
≥20 mut/Mb 9 (13)
6–19 mut/Mb 32 (46.4)
≤ 5 mut/Mb 28 (40.6)
PDL1 tumor proportion score
0 18 (26.1)
1–49% 28 (40.6)
≥50 17 (24.6)
Not able to assess 6 (8.7)
Microsatellite stability
Stable 61 (88.4)
Unstable 6 (8.7)
Unknown 2 (2.9)
Best Response
CR 14 (20.3)
PR 22 (31.9)
SD 12 (17.4)
PD 21 (30.4)
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3.3 Biomarkers and Mutational assay
The majority of the tumor samples (65.2%) had a positive PDL‐1 expression represented as a tumor proportion score (TPS) ≥1%. 90% of the tumors were microsatellite stable, and the average TMB was 12.6 (range 0–117). 13% of patients had TMB ≥20 mut/Mb and 46.4% tumors had TMB between 6–19 mut/Mb. The NGS panel detected TP53 as the most common (62.3%) tumor mutation. It was followed by CDKN1B/2A (40.5%), NOTCH (33.3%), and PIK3CA/2B (33.3%) mutations. STK11 mutation was found in 16% of patients. TMB did not correlate to smoking status or pack years (Table 2, Figure 1, Figure 2).
FIGURE 1 Percentage of patients with mutations in cBioPortal and this study. (A) NSCLC cohort in both studies with genomic alterations associated with smoking. (B) Genomic alterations involving PIK3/AKT/mTOR pathway. (C) Alterations implicated in homologous recombinant repair. (CBP: cBioPortal)
FIGURE 2 Mutational analysis of patients receiving immunotherapy grouped based on radiologic response, in the order of mutational load and frequency of mutations
Tumor mutations commonly associated with smoking (BRAF, JAK2, JAK3, NOTCH1, TP53) were higher in the study population compared to cBioPortal database metastatic solid tumor cohorts. 14 , 15 There was similar difference on evaluation of genomic alterations involving PIK3/AKT/mTOR pathway and alterations implicated in homologous recombinant repair. BRCA1, MTOR, and PTEN mutations were, however, less common in the study group compared to the trial cohort.
3.4 Response and outcome by PDL1 expression and TMB
TMB was not associated with smoking status or pack years. Patients with high TMB (≥20 mut/Mb) had an overall radiologic response rate (CR+PR) of 55.6% compared to 51.7% in low‐intermediate TMB group (p = 0.83). Median PFS was higher in high TMB compared to the low‐intermediate group and the results reached statistical significance (median not reached vs. 26 weeks; HR=0.37. 95%CI 0.13, 1.05). Although there was improvement in PFS (median 53 vs. 26 weeks, HR=1, 95%CI 0.37, 2.72) this was not statistically significant when the FDA‐approved cut off of ≥10mut/Mb for ICI use was used to identify high TMB. Radiologic responders were identical in both groups. (0.52% vs. 0.52%, OR = 1, p = 1). PDL1 expression was not associated with radiologic response, but there was a trend toward improved PFS in patients with tumors expressing PDL1 (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). There was no significant correlation between size change of the target lesion with ICI therapy and absolute TMB values (R2 = 0.023) (Figure 3, Table 3).
FIGURE 3 Kaplan‐Meier graphs depicting progression‐free survival in patients based on tumor samples showing (A) High TMB and low/intermediate TMB; (B) PDL1 expression; (C) Presence of IRAEs; (D) Presence of PIK3 mutation; (E) Presence of FGFR mutation; (F) Presence of BRAF mutation
TABLE 3 Table showing ORR based on various factors with odds ratio calculated using logistic regression model
Variable Total Responders (CR/PR) n (%) Non‐responders (SD/PD) n (%) Overall response rate OR 95% CI
All patients 69 36 (52.2) 33 (47.8) 52.2%
Age <65 40 19 (47.5) 21 (52.5) 47.5% 0.64 (0.24–1.68)
Age >65 29 17 (58.6) 12 (41.4) 58.6%
Male 36 16 (44.4) 20 (55.6) 44.4% 1.92 (0.74–5.02)
Female 33 20 (60.6) 13 (39.4) 60.6%
Smoker 54 26 (48.1) 28 (51.9) 48.1% 2.15 (0.64–7.14)
Non‐smoker 15 10 (66.7) 5 (33.1) 66.7%
IRAE present 34 19 (55.9) 15 (44.1) 55.9% 0.75 (0.29–1.92)
IRAE absent 35 17 (48.6) 18 (51.4) 48.6%
High TMB 9 5 (55.6) 4 (44.4) 55.6% 1.17 (0.29–4.78)
Low/int TMB 60 31 (51.7) 29 (48.3) 51.7%
TMB <10 46 24 (52.2) 22 (47.8) 52.2% 1.00 (0.36–2.72)
TMB ≥10 23 12 (52.2) 11 (47.8) 52.2%
PDL1 0% 18 6 (33.3) 12 (64.7) 33.3% 0.45 (0.12–1.68)
PDL1 >1% 45 25 (55.6) 20 (44.4) 55.6%
PIK3 mutated 23 16 (69.6) 7 (30.4) 69.6% 0.34 (0.12–0.97)
PIK3 wild type 46 20 (43.5) 26 (56.5) 43.5%
FGFR mutated 16 13 (72.2) 5 (27.8) 72.2% 0.32 (0.98–1.01)
FGFR wild type 51 23 (45.1) 28 (54.9) 45.1%
ROS1 mutated 10 9 (90.0) 1 (10.0) 90.0% 0.09 (0.01–0.79)
ROS1 wild type 59 27 (45.8) 32 (54.2) 45.8%
BRAF mutated 5 3 (60.0) 2 (40.0) 60.0% 0.71 (0.11–4.54)
BRAF wild type 64 33 (51.6) 31 (48.4) 51.6%
STK 11 mutation 11 4 (36.4) 7 (63.6) 36.4% 2.15 (0.57–8.17)
STK11 wild type 58 32 (55.2) 26 (44.8) 55.2%
Bold indicates statistically significant values.
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3.5 Response and outcome by tumor mutations
The presence of BRAF mutation conferred shorter PFS with immunotherapy (median 17 vs. 39 weeks. HR = 0.35. 95%CI 0.14, 0.91) but had no significant association with radiologic response. STK11 mutation did not have a significant impact on PFS (median 30 vs. 39 weeks, HR=0.88. 95%CI 0.39, 2.0) or radiologic response (OR = 1.61, p = 0.58). Presence of KRAS mutations also did not show significant impact on PFS (median 48 vs. 38 weeks, HR=1.27, 95%CI 0.62, 2.58) or radiologic response (OR = 1.12, p = 0.84) (Figure 3, Table 3).
Statistically significant improvement in PFS was observed in the PIK3 mutated (PIK3CA/PIK3C2B) group (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). (Figure 3) This was independent of TMB status or PDL1 expression status (HR 3.24, p = 0.016). Patients with PIK3 mutations had a higher overall response rate (ORR) than the unmutated group (69.6% vs. 43.5%, OR 0.34; p = 0.045). PIK3 mutated patients also had a higher risk of developing IRAEs (73.9% vs. 37%, OR = 0.21 p = 0.005), but the presence of mutation did not associate with TMB, PDL1 expression or microsatellite stability status ruling out collinearity.
There was a difference in ORR with FGFR mutations (72.2% vs 45.1%, OR 0.32; p = 0.05) and ROS1 mutation (90% vs. 45.8%, OR 0.09; p = 0.029). With FGFR mutation, there was a trend toward statistical significance for PFS with immunotherapy (median 39 vs. 30 weeks. HR = 1.84. 95%CI 0.90, 3.76), which was not seen with ROS1 mutation.
3.6 Response and outcome (others)
There was no statistically significant difference in radiologic response and PFS with ICI therapy based on smoking status, ICI drug, MSS status, incidence of IRAEs, or age (below and above 65 years of age).
4 DISCUSSION
Our study was aimed at evaluating clinicopathologic characteristics and outcomes in a subset of population with the highest incidence of cancer in the country and often underrepresented in clinical trials. The outcomes with immunotherapy, incidence of iRAEs and biomarker profiling of these patients are poorly understood. With the current data available only from a carefully selected clinical trial population, many biomarkers that could be effective in such selected population might have been overlooked. The study also looked at potential markers of immunotherapy response in this patient population (90).
The prevalence of smoking and secondhand smoke exposure was high in the study group. The study did not find association of smoking status with TMB. Nearly half (47.8%) of the patients experienced any degree of IRAEs. The median tumor mutation burden was 12.6 mutations/Mb which was at least twofold to fourfold compared to other similar studies. 16 , 17 Our results show the prevalence of PDL1 expression, TMB in our study group are similar to ones seen in previous clinical trials. Compared to historic cohorts, the prevalence of PIK3/AKT/mTOR pathway and homologous recombinant repair alterations were higher in the study group. Smoking associated tumor genomic alterations was also significantly higher compared to similar cohorts.
High‐tumor mutational burden, and the presence of PIK3 mutation conferred better progression‐free survival with immunotherapy across cancer types. This PFS benefit seen in PIK3 mutated patients was independent of PDL1 status or TMB. The effect of PDL1 expression and FGFR mutation on PFS trended toward statistical significance. The presence of PIK3 mutation and ROS1 mutation also had a statistically significant favorable impact on the best overall radiologic tumor response while with FGFR mutation, this trended toward statistical significance. The high incidence of IRAEs in the PIK3 mutated group also points toward possible increased PDL1 inhibitor activity. STK11 mutation, which was previously implicated in immunotherapy resistance, did not significantly affect immunotherapy response or outcomes. Although the absolute numbers were small, patients with BRAF mutations had a poor outcome with immune therapy.
The PIK3/AKT/mTOR (PAM) pathway is considered a master regulator of cancer and plays a vital role in tumor growth, proliferation, angiogenesis, and cell survival. 18 PIK3CA is the most studied among PIK3 mutations, with amplification or clustering of somatic mutations occurring in up to 30% of endometrial, breast, ovarian, and colon cancers while PIK3CB is found in thyroid and lung cancers. 19 PI3KCA/CB mutations are primarily activating, while the pathway inhibiting PIK3R1 mutations are mostly inactivating. 20 These mutations were also implicated in chemotherapy and HER2 blocker resistance. 21 , 22 The pathway, more importantly, plays a stimulatory role in PDL1 transcription and expression on tumor cells. 23 , 24 Despite the abundance of laboratory and animal data, clinical data linking various PIK3 protein mutations and immunotherapy responses are lacking.
The study has limitations with small sample size, short follow‐up period and being a single‐center study. Most of the patients who received ICI at the institution were not included in the final analysis due to incomplete data or loss to follow up making the need of prospective trials important. The results should prompt further evaluation of these potential biomarkers and more widespread real‐world data publications.
5 CONCLUSION
The study characterizes the ICI response, IRAEs, and mutational profile in a population with high prevalence of smoking and the highest cancer incidence and mortality in the country. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway were higher in the study group compared to similar cohorts. The previously reported positive evidence for TMB and PDL1 expression as ICI biomarkers were replicated in this study. The presence of PIK3 mutation conferred better progression‐free survival and radiologic response with immunotherapy across cancer types. Although conflicting evidence exists on using these markers across cancers for patient selection, these could still be relevant in specific target populations with significant risk factors like smoking in our population. More extensive studies and long‐term follow‐up data are needed to confirm the clinical validity and role of individual mutations in immunotherapy response. Furthermore, more real‐world data is needed to help identify specific biomarkers based on population and risk factors.
CONFLICTS OF INTEREST
Authors Aasems Jacob, Jianrong Wu, Jill Kolesar, Eric Durbin, Aju Mathew and Susanne Arnold express no conflicts of interest. Aman Chauhan has received research grant from BMS, Clovis, Lexicon; Advisor Lexicon, Ipsen.
ETHICAL APPROVAL AND INFORMED CONSENT
University of Kentucky Institutional Review Board approved the study (IRB# #49450 on 8/9/2019)
The Office of Research Integrity under IRB, University of Kentucky authorized waiver of informed consent as the study involved no more than minimal risks for the subjects and their privacy.
DATA AVAILABILITY STATEMENT
Raw data were generated at University of Kentucky and Kentucky Cancer Registry. Derived data supporting the findings of this study are available from the corresponding author AJ on request. | ATEZOLIZUMAB, IPILIMUMAB, NIVOLUMAB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY | 33619913 | 19,777,723 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYCLOPHOSPHAMIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33620515 | 19,002,502 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mental status changes'. | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYCLOPHOSPHAMIDE, HYDRALAZINE HYDROCHLORIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33620515 | 20,043,816 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CYCLOPHOSPHAMIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33620515 | 19,002,502 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rash'. | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CREATININE, CYCLOPHOSPHAMIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33620515 | 19,100,880 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vasculitis'. | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CREATININE, CYCLOPHOSPHAMIDE, PREDNISONE | DrugsGivenReaction | CC BY | 33620515 | 19,100,880 | 2021-07 |
What was the dosage of drug 'CORTICOSTEROID NOS'? | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
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Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | UNK, 2 /DAY | DrugDosageText | CC BY | 33620515 | 19,039,551 | 2021-07 |
What was the dosage of drug 'CREATININE'? | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 2 MG/DL | DrugDosageText | CC BY | 33620515 | 19,100,880 | 2021-07 |
What was the outcome of reaction 'Clostridium difficile colitis'? | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33620515 | 20,043,816 | 2021-07 |
What was the outcome of reaction 'Escherichia bacteraemia'? | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33620515 | 20,043,816 | 2021-07 |
What was the outcome of reaction 'Human herpesvirus 8 infection'? | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33620515 | 20,043,816 | 2021-07 |
What was the outcome of reaction 'Urosepsis'? | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
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Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33620515 | 20,043,816 | 2021-07 |
What was the outcome of reaction 'Vasculitis'? | Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.
Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) (Wegener’s), and eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss syndrome), all pauci-immune vasculitides which share clinical features and are characterized by the presence of ANCA [1]. Serious organ-threatening disease involvement with rapidly progressive glomerulonephritis, diffuse alveolar hemorrhage but also gastrointestinal, cardiac, and neurologic disease can occur [2]. The standard treatment for severe organ-threatening disease is glucocorticoids, followed by induction therapy with cyclophosphamide, or rituximab [3]. A serious consequence of immunosuppression is opportunistic infections. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm that has been associated with human herpesvirus 8 (HHV8) [4–6]. Over the years, there have been four recognized types of KS: classic, endemic, iatrogenic (immunosuppression or transplant associated), and epidemic [4–6]. We report a case of hydralazine-induced AAV with pulmonary-renal syndrome complicated by iatrogenic KS during treatment. We performed a comprehensive search through MEDLINE using the following keywords: Kaposi sarcoma, vasculitis, ANCA vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, Takayasu arteritis, polymyalgia rheumatica, giant cell arteritis, polyarteritis nodosa, and Behcet's disease. We included articles published in English so that details could be extracted. This resulted in exclusion of 5 non-English articles (1 case in AAV and 4 cases in giant cell arteritis). The references of the individual articles were also examined to find other key references. The aim of the review was to identify common factors which may better aid in identifying patients at risk of this rare complication. Based on our review, glucocorticoids appear to be an important risk factor for KS in patients with vasculitis.
Case presentation
A 77-year-old man of Italian American descent was referred to us for evaluation of AAV. He presented to an outside facility with a 30-lb weight loss, cough, scant hemoptysis, and worsening dyspnea on exertion. Laboratory evaluation showed acute kidney injury with a creatinine of 2.58 mg/dL (baseline 1.0 mg/dL) and BUN of 30 mg/dL, acute anemia with hemoglobin 6.1 g/dL. During hospitalization, he developed rapidly progressive renal failure requiring initiation of hemodialysis, in addition to gross hemoptysis. Serologies included a positive anti-nuclear antibody (ANA 1:320), positive double-stranded DNA (dsDNA 1:40), p-ANCA of 1:1280, MPO 52 IU (> 1 IU positive), and negative anti-glomerular basement membrane antibody (Table 1). Other serologies including SSA, SSB, Smith, RNP, centromere, Scl-70, DRVVT, cardiolipin, beta-2-glycoprotein, ribosomal P, anti-chromatin antibodies were negative. Histone antibodies were not tested. Bronchoscopy confirmed diffuse alveolar hemorrhage. A kidney biopsy was done but was non-diagnostic, showing acute tubular necrosis and mild mesangial matrix expansion with 4 out of 13 glomeruli which were globally sclerotic with mild parenchymal scarring. The patient was treated for a diagnosis of MPA with pulse does steroids, seven sessions of plasmapheresis followed by intravenous cyclophosphamide 400 mg/m2 during hospitalization. He was able to successfully come off hemodialysis after 1.5 weeks with a new baseline creatinine of 2 mg/dL. Four weeks later, he was treated with cycle 2 of intravenous cyclophosphamide 400 mg/m2.Table 1 Laboratory findings at initial diagnosis of microscopic polyangiitis (MPA), and, later when diagnosis of Kaposi Sarcoma (KS) was made
Laboratory (reference range) Value
At initial diagnosis MPA At diagnosis KS
WBC (4.16 – 9.95 × 10E3/uL) 11.5 19.81
Absolute Neutrophil Count (1.80 – 6.90 × 10E3/uL) 9.8 18.22
Absolute Lymphocyte Count (1.30 – 3.40 × 10E3/uL) 0.58 0.68
Hemoglobin (13.5–17.1 g/dL) 6.1 11.6
Platelet Count (143 – 398 × 10E3/uL) 176 259
Sedimentation Rate By Modified Westergren (< OR = 20 mm/h) > 120 97
C-Reactive Protein (< 0.8 mg/dL) 28.9 1.19
Urea Nitrogen (7–22 mg/dL) 48 86
Creatinine (0.60–1.30 mg/dL) 2.58 2.95
Calcium (8.6–10.4 mg/dL) 9.0 8.2
Phosphorus (2.3–4.4 mg/dL) 3.3 5.5
Total Protein (6.1–8.2 g/dL) 5.8 5.9
Albumin (3.9–5.0 g/dL) 2.2 3.1
Alkaline Phosphatase (37–113 U/L) 43 217
Aspartate Aminotransferase (13–47 U/L) 28 88
Alanine Aminotransferase (8–64 U/L) 18 58
Procalcitonin (< 0.10 ug/L) 1.53 8.30
Immunoglobulin G serum (nl 726–1521 ml/dL) Not tested 533
Immunoglobulin A serum (nl 87–426 ml/dL) Not tested 201
Immunoglobulin M serum (nl 44-277 ml/dL) Not tested 92
HIV Negative Negative
dsDNA Ab Positive, 1:40 Negative
C-ANCA (< 1:20 titer) Negative Negative
P-ANCA (< 1:20 titer) 1:1280 Negative
Proteinase-3 Ab Negative Negative
Myeloperoxidase Ab 52 (> 1 positive) < 20.0 (> 20 positive)
C3 (76–165 mg/dL) 126 132
C4 (14–46 mg/dL) 34 35
Urinalysis
Protein/Creatinine Ratio,Ur (0.0–0.4) 0.82 0.3
RBC per HPF (0–2 cells/HPF) > 20 0
WBC per HPF (0–4 cells/HPF) 0–2 0
Hyaline Casts (0–2/LPF /LPF) 0 11–20
Approximately 2 months after starting treatment, he developed a new lower extremity rash (Fig. 1a). Prednisone was increased from 40 to 45 mg by his local rheumatologist with some improvement. However, given persistent symptoms, the patient sought a second opinion at our tertiary care medical center. At the time of evaluation, he was on prednisone 45 mg daily and last cyclophosphamide (dose 2, 400 mg/m2) infusion had been administered 2 weeks prior. Apart from the rash, he denied any symptoms. Laboratory parameters, including renal function, were stable. Medication review revealed that he had been on treatment with hydralazine for hypertension for more than 1 year prior, and, given association of hydralazine with AAV, hydralazine was discontinued. Prednisone was lowered to 35 mg. Rituximab was discussed given severe manifestations of vasculitis but given positive hepatitis B core antibody, recommendation was made for evaluation with infectious diseases first. Unfortunately, 1 month later, he was hospitalized for mental status changes from urosepsis with Escherichia coli bacteremia. He was on prednisone 35 mg daily at the time. Treatment was complicated with Clostridium difficile colitis. During that hospitalization, further testing was pursued (Table 1). In addition, given lack of improvement in the lower extremity rash, a skin biopsy was obtained from his left thigh and his left foot. This showed an atypical HHV8-positive vascular proliferation without vasculitis consistent with KS (Fig. 1b–d). Testing for human immunodeficiency virus (HIV) was negative. While the initial plan was to start treatment with rituximab based on the severity of the manifestations of vasculitis, given the numerous infectious complications and hospitalizations, along with the absence of any evidence of active vasculitis, the recommendation was to hold off on immunosuppressive therapy. Furthermore, given that there was suspicion of this being hydralazine-induced, it was felt discontinuation of the trigger may also help. After discussion with the different specialists, and the patient, the decision was made to gradually taper prednisone and monitor closely without additional immunosuppressive therapy. He was also referred to oncology for co-management. He did not have any clinical evidence of gastrointestinal mucosal involvement of his KS and was started on treatment with topical imiquimod cream 5%. Chemotherapy was not considered since the etiology of his KS was felt to be due to immunosuppression as well as his recent history of multiple infections, renal insufficiency, and, immunosuppression was being lowered. He remains on prednisone 10 mg daily with adequate control of vasculitis and improvement in skin lesions. He continues to follow with rheumatology and oncology. Since discontinuation of cyclophosphamide and lowering prednisone, hypogammaglobulinemia has resolved with immunoglobulin G of 825 mg/dL (range 600–1540 mg/dl). He has had no further infectious complications and his KS remains clinically indolent.Fig. 1 a Multiple violaceous, coalescent, nodular lesions on the foot and ankle. b Histologic sections of skin from biopsy of a thigh lesion show dermis filled with irregular, somewhat jagged blood-filled vascular spaces adhering to collagen bundles and surrounding native blood vessels (so-called ‘promontory sign’, see arrows). Hematoxylin and eosin, 200x. c Performed CD34 immunohistochemistry strongly highlights irregular, infiltrative vascular spaces. CD34 immunohistochemistry, 200x. d Performed HHV8 immunohistochemistry highlights tumor endothelial cell nuclei and confirms the diagnosis of Kaposi’s sarcoma. HHV8 immunohistochemistry, 200x
Discussion
We present a rare case of MPA, possibly hydralazine-induced, with pulmonary-renal syndrome complicated by the development of KS during treatment with systemic glucocorticoids and cyclophosphamide.
One of the unusual aspects of this case was the possibility of the manifestations of AAV being hydralazine-induced. Severe manifestations including pulmonary-renal syndrome have been described in hydralazine-induced vasculitis [7–12]. A clue to this entity is the serologic profile which often includes other antibodies often seen in systemic lupus erythematosus (which hydralazine can also induce) in addition to ANCA (usually p-ANCA, MPO) [12]. Other positive serologies that have been reported with hydralazine-induced vasculitis are ANA, anti-histone antibodies, positive dsDNA, hypocomplementemia and anti-phospholipid antibodies [9, 12]. Our patient also had positive ANA and low titer dsDNA at initial diagnosis. While other connective tissue disease serologies, complements and testing for anti-phospholipid antibodies was performed, anti-histone antibody was not tested. The possibility of hydralazine-induced vasculitis was missed and considered few months later when he was evaluated at our facility for a second opinion. In most cases of serious organ manifestations, even though hydralazine was thought to be the trigger, in addition to withdrawal of the offending medication, immunosuppressive therapy including glucocorticoids, cyclophosphamide or rituximab were used [7]. In our case, the management was complicated by numerous infectious complications including KS.
The risk factors for KS include infection with HHV8, HIV, and immunosuppression [4–6, 13–15]. Our patient best fits as an example of iatrogenic KS, which has been widely reported in immunosuppressed patients, including those with organ transplantation [5, 16]. Despite the wide-spread use of immunosuppressive medications in systemic rheumatic diseases including vasculitis, the association of KS is rare, indicating there are other risk factors at play [17, 18].
A review of the literature evaluating KS in AAV, identified 10 additional cases whose findings are summarized in Table 2 [19–28]. The majority of the reports (70%) are in patients with GPA, with two reports in MPA and one in EGPA (Table 2). Age range was from 46 to 78 years with 60% of the cases being in men (Table 2). Time to onset of KS lesions ranged from 6 weeks to 11 months (Table 2). One reported case in the literature described coincidental occurrence of KS and GPA with worsening KS during treatment [26]. In another report, KS lesion on an ear was noted 19 years after diagnosis but, unusually, this patient had been given several different inflammatory diagnoses over the years including polyarteritis nodosa, neurosarcoidosis and finally, GPA [19]. All patients were still on systemic glucocorticoids and intravenous methylprednisolone were administered in 80% reported cases (Table 2). Adjunctive immunosuppressive therapy in patients who developed KS included cyclophosphamide (9 cases), azathioprine (3 cases) and mycophenolate mofetil (1 case), likely reflecting commonly used treatments in AAV given most cases had pulmonary and renal manifestations (Table 2). In all except one case, cutaneous involvement from KS was present, most frequently on the trunk and extremities. One case reported isolated KS of the gastrointestinal tract in a patient with GPA [28]. HHV-8 was positive in 6 of 7 cases where the information was provided (Table 2). The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids (Table 2). In some cases, chemotherapy and radiation therapy were also used to treat KS (Table 2). The status of the vasculitis after lowering immunosuppressive therapy was variable with some cases of relapses (Table 2). The patient in this case also presented many management challenges. Though hydralazine was thought to be the likely trigger of vasculitis, given the severe manifestations with pulmonary-renal syndrome, treatment with rituximab was considered. However, the patient had positive hepatitis B core antibody and recommendation was to start prophylaxis prior to treatment. Meanwhile, he developed numerous infectious complications including urosepsis, Clostridium difficile requiring hospitalizations which delayed initiation of rituximab. Finally, he also developed infectious complication of KS from HHV-8. Given that there was no evidence of active vasculitis, that hydralazine which may have been a trigger was discontinued, and risks of further immunosuppression, decision was made to use glucocorticoid monotherapy, lower prednisone gradually monitor closely. He clinically improved with reduction in glucocorticoid doses, discontinuation of cyclophosphamide, and topical imiquimod. To date, there has been no recurrence of vasculitis which may be in part from the discontinuation of hydralazine.Table 2 Summary of literature review of ANCA-associated vasculitis with Kaposi sarcoma
Author Age, years/sex Diagnosis AAV Organ involvement ANCA type Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV-8 status Treatment Outcome
Our case 77/M Drug-associated MPA Pulmonary-renal syndrome p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 6 Weeks Skin lesions on upper and lower extremities HIV negative, HHV-8 positive Withdrawal of cyclophosphamide, lower prednisone, imiquimod topical Regression KS, vasculitis in remission
Fatma et al.[20] 72/F MPA Pulmonary-renal syndrome Positive p-ANCA, MPO Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk, lower extremities, face, neck HIV negative, HHV-8 positive Withdrawal of immunosuppression Regression KS, relapse vasculitis with alveolar hemorrhage
Biricik et al.[27] 71/M MPA Pulmonary-renal syndrome p-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 3 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Decrease glucocorticoid dose, cyclophosphamide discontinued, radiation therapy Regression KS, vasculitis status not provided
Erban and Sokas[21] 78/M GPA Pulmonary-renal syndrome, chronic sinusitis, arthralgia Not tested Glucocorticoids (oral methylprednisolone), oral cyclophosphamide 10 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoid discontinued, cyclophosphamide continued, proton beam radiation to the feet Regression KS, death from cardiogenic shock during cardiac bypass procedure
Deschenes et al.[22] 54/M GPA Sinusitis, cavitary pulmonary lesions c-ANCA, PR3 Glucocorticoids (IV then oral prednisone), oral cyclophosphamide 8 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 status not provided Glucocorticoids tapered off, cyclophosphamide reduced then discontinued after 20 months Regression KS, vasculitis in remission
Hoff and Rødevand[19] 46/M GPA Cranial neuropathies, sinusitis, arthritis, lung nodules Negative c-ANCA, p-ANCA
MPO/PR3 not tested
Glucocorticoids, IV cyclophosphamide (stopped due adverse effects), methotrexate ~ 19 Years Skin lesion on ear HIV and HHV-8 status not provided None Died of bladder cancer, vasculitis improved
Bouattar et al.[23] 50/F GPA Glomerulonephritis, L nasal ulceration c-ANCA positive; MPO and PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 18 Weeks Skin lesions on trunk, upper and lower extremities HIV negative, HHV-8 positive Discontinuation of cyclophosphamide, decrease glucocorticoid dose Regression KS followed by recurrence, worsening renal function requiring dialysis, death from DIC
Saxena et al.[25] 66/F GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 5 Months Skin lesions on trunk and upper and lower extremities HIV status not provided, HHV-8 positive Cyclophosphamide continued for another month then switched to azathioprine, prednisone gradually tapered, azathioprine stopped for worsening KS, IV doxorubicin Regression KS, vasculitis in remission
Kılıç et al. [26] 70/F GPA Nasal septal perforation, glomerulonephritis, pulmonary nodules c-ANCA positive; MPO/PR3 not tested Glucocorticoids (IV followed by oral prednisone), IV cyclophosphamide 0 (Present at diagnosis but worse at 12 weeks) Skin lesions on left lower extremity HIV negative, HHV-8 negative Glucocorticoids decreased, cyclophosphamide discontinued, radiation therapy, systemic chemotherapy (treatment not specified) Not provided
Endo and Nagata[28] 73/M GPA Not provided Not provided Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide 4 cycles) then azathioprine 11 Months Gastrointestinal ulcerations (upper and lower tract) HIV negative, HHV-8 positive Corticosteroids tapered from 11 mg per day to 6 mg per day, azathioprine continued Ulcerations and lesions improved, vasculitis in remission
Berti et al. [24] 67/M EGPA Glomerulonephritis, sinusitis, asthma, nasal polyposis Not provided Glucocorticoids (oral), mycophenolate mofetil Not provided Cutaneous HIV negative, HHV-8 positive Mycophenolate mofetil was discontinued, prednisone continued (5 mg per day) Regression KS, vasculitis in remission
AAV anti-neutrophil cytoplasmic antibody-associated vasculitis, ANCA anti-neutrophil cytoplasmic antibody, EGPA eosinophilic granulomatosis with polyangiitis, F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Given the rarity of KS in AAV, we also extended our literature review to other forms of systemic vasculitis (Table 3). We found reports in giant cell arteritis (4 cases), Behcet’s disease (2 cases), polymyalgia rheumatica (3 cases), IgA vasculitis (previously Henoch-Schonlein purpura, 1 case), and cutaneous vasculitis (1 case) [17, 29–37]. In all cases, patients were on glucocorticoid therapy (Table 3). As in the case of patients with AAV, cutaneous involvement from KS was present, most frequently on the trunk and extremities. There was a case of systemic involvement with KS of the gastrointestinal tract in a patient with Behcet’s disease [34]. The majority of cases improved with reduction or withdrawal of immunosuppressive therapy, especially glucocorticoids, with some relapses of the underlying vasculitis in some cases (Table 3).Table 3 Literature review of Kaposi Sarcoma (KS) in other forms of systemic vasculitis
Author Age, years/Sex Diagnosis Immunosuppression Time to onset of KS Areas affected by KS HIV and HHV8 status Treatment Outcome
Klepp et al. [17] 79/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 7 Months Skin lesions lower extremities and eyelid HIV status not provided, HHV-8 status not provided Radiotherapy Regression of KS, patient died suddenly of unknown cause
Vincent et al. [33] 84/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Months Skin lesions on lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
Brambilla et al. [37] 72/F Polymyalgia rheumatica Glucocorticoids (oral prednisone) 4 Years (was on 4 mg daily for 4 years) Skin lesions on trunk, upper and lower extremities, leg lymphedema HIV negative, HHV-8 positive Gradually discontinue prednisone, taxol Partial regression of KS, developed Merkel cell carcinoma requiring additional treatment
Leung et al. [29] 70/F Giant cell arteritis Glucocorticoids (oral prednisone) 5 Months Skin lesions upper and lower extremities, neck, lips, back HIV status not provided, HHV-8 status not provided Decrease in prednisone doses Regression of KS, no flares of giant cell arteritis
Di Giacomo et al. [30] 69/M Giant cell arteritis Glucocorticoids (oral prednisone) 3 Months Skin lesions lower extremities HIV status not provided, HHV-8 status not provided Decrease in prednisone, change to methyl-fluoro-prednisolone Status of KS not available, flare of giant cell arteritis
Soria et al. [32] 45/F Giant cell arteritis Glucocorticoids (oral prednisone) 3 Years Skin lesions upper and lower extremities, face, trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone, vincristine, radiation therapy Regression of KS, status of giant cell arteritis not provided
Kuttikat et al. [35] 79/F Giant cell arteritis Glucocorticoids (oral prednisolone) 6 Weeks Skin lesions on trunk, lower extremities HIV negative, HHV-8 positive Taper of prednisone with discontinuation Resolution of KS, no flares of giant cell arteritis
Kotter et al. [34] 29/M Behcet’s disease Glucocorticoids (oral prednisolone), cyclosporine A, azathioprine 3 Years Skin, gastric mucosa, hard palate, pulmonary HIV negative, HHV-8 positive Discontinuation of azathioprine and cyclosporine A, taper prednisolone Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Mezalek et al. [36] 44/M Behcet’s disease Glucocorticoids (IV followed by oral prednisolone), IV cyclophosphamide × 6 then azathioprine 10 Months Skin lesions on lower extremities HIV negative, HHV-8 positive Discontinuation of azathioprine, decrease glucocorticoid dose Ocular disease flared requiring treatment with interferon alpha, both diseases in remission
Schulhafer et al. [31] 61/M IgA vasculitis Glucocorticoids (intravenous prednisolone, oral prednisone), chlorpropamide 6 Months Skin lesions trunk HIV status not provided, HHV-8 status not provided Decrease in prednisone Regression of KS, IgA vasculitis flared requiring repeat prednisone treatment followed by discontinuation
Vincent et al. [33] 79/F Leukocytoclastic
vasculitis
Glucocorticoids (oral prednisone) 3 Months Skin lesions on trunk, upper and lower extremities HIV status not provided, HHV-8 positive Not provided Not provided
F Female, GPA granulomatosis with polyangiitis, HHV-8 human herpesvirus 8, HIV human immunodeficiency virus, IV intravenous, KS Kaposi sarcoma, M male, MPA microscopic polyangiitis, MPO myeloperoxidase, PR3 Proteinase 3
Both the cellular and humoral arms of the immune system have been implicated in the control of KS. Immunosuppression is a common theme noted in KS, whether due to innate problems of host immunity, or, due to factors that lead to induced immunosuppression [38]. For instance, the rate of KS in acquired immunodeficiency syndrome (AIDS) patients is inversely proportional to the CD4 count [38]. In non-AIDS associated KS, based on our review of the literature, in patients with rheumatic conditions, glucocorticoids appear to be a consistent risk factor for KS irrespective of other immunosuppressive therapy [39]. Several potential mechanisms have been proposed to explain the association of KS from immunosuppression, including higher expression of chemokine receptors and growth factors, or culprit viral genes. However the data is limited and information is extrapolated from the post-transplantation KS literature [40]. Other possibilities could be the effects of glucocorticoids on lymphocyte depletion [22]. Some studies have found a direct effect of glucocorticoids in stimulating the development and growth of KS [41, 42]. Exogenous glucocorticoids can stimulate the proliferation of spindle cells in KS by upregulation of glucocorticoid receptors [41, 42]. They can also cause direct activation of HHV-8 [41, 42].
Finally, B-cells are latent reservoirs of HHV-8 [6]. While all reported cases of KS in AAV to date have been in patients treated with cyclophosphamide, azathioprine or mycophenolate mofetil, how the increased use of rituximab will affect risk of KS in AAV remains unclear. A recent report included 5 patients who developed KS after treatment with rituximab for their autoimmune conditions (none with AAV) [43]. All were on treatment with glucocorticoids (prednisone dose 10 mg to 35 mg). Time from rituximab to HHV-8 ranged from 3 to 11 months. Four of 5 patients had cutaneous manifestations but gastrointestinal, lung, urogenital disease, pleural effusion and lymphoma were also reported [43]. Two patients required treatment with radiation or chemotherapy [43].
In summary, despite immunosuppression in vasculitis, KS appears to be a rare complication of therapy. It is important to recognize KS as an infectious complication in patients with AAV. The violaceous, nodular lesions in KS, can be mistaken for the palpable purpura from cutaneous vasculitis which also affect the upper and lower extremities [44]. The majority of the cases were within the first year of treatment and the skin was the most frequently affected organ in KS. Glucocorticoid therapy appears to be an important risk factor. Lowering immunosuppression, especially glucocorticoids appears to be beneficial in causing regression of KS. However, this can be challenging since decreasing immunosuppression to help KS could potentially result in recurrence of the underlying systemic vasculitis. A multi-disciplinary approach is important along with individualizing the decision to lower immunosuppression with the possibility of relapse of vasculitis.
Author contributions
All of the authors made contributions to the content of this article. The literature review and initial draft of the manuscript were prepared by BT and TK. Clinical and histopathologic images were provided by AS and GS. All authors commented on the manuscript. All authors read and approved the final manuscript as submitted and take full responsibility for all aspects of this manuscript.
Funding
Not applicable.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no conflicts of interest/competing interests.
Consent for publication
Consent for publication was obtained from the patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33620515 | 19,100,880 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | ALFACALCIDOL, BELIMUMAB, CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE SULFATE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL\MYCOPHENOLATE MOFETIL HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33622323 | 19,076,387 | 2021-02-23 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | ALFACALCIDOL, BELIMUMAB, CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE SULFATE, METHYLPREDNISOLONE SODIUM SUCCINATE, MYCOPHENOLATE MOFETIL\MYCOPHENOLATE MOFETIL HYDROCHLORIDE, PREDNISOLONE, RITUXIMAB, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33622323 | 19,076,387 | 2021-02-23 |
What is the weight of the patient? | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | 44.2 kg. | Weight | CC BY | 33622323 | 20,220,667 | 2021-02-23 |
What was the administration route of drug 'CYCLOPHOSPHAMIDE'? | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33622323 | 19,072,142 | 2021-02-23 |
What was the administration route of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33622323 | 19,076,387 | 2021-02-23 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33622323 | 19,072,142 | 2021-02-23 |
What was the dosage of drug 'HYDROXYCHLOROQUINE SULFATE'? | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | 200 MILLIGRAM, DAILY | DrugDosageText | CC BY | 33622323 | 19,076,387 | 2021-02-23 |
What was the dosage of drug 'HYDROXYCHLOROQUINE'? | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | 200 MILLIGRAM DAILY; | DrugDosageText | CC BY | 33622323 | 19,072,142 | 2021-02-23 |
What was the dosage of drug 'METHYLPREDNISOLONE SODIUM SUCCINATE'? | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | 1 GRAM, QD, PULSE THERAPY | DrugDosageText | CC BY | 33622323 | 19,076,387 | 2021-02-23 |
What was the dosage of drug 'MYCOPHENOLATE MOFETIL\MYCOPHENOLATE MOFETIL HYDROCHLORIDE'? | Childhood-onset systemic lupus erythematosus with trisomy X and the increased risk for bone complications: a case report.
BACKGROUND
Systemic lupus erythematosus is a multi-organ inflammatory autoimmune disease; immune complexes are part of the pathogenesis, but not entirely responsible. Trisomy X is the most common female chromosomal abnormality and the role of an additional X chromosome in the development of systemic lupus erythematosus is well recognized. However, the potential complications and optimal management of childhood lupus with trisomy X remain unclear. Herein, we describe a case of childhood-onset systemic lupus erythematosus associated with severe bone complications presumably secondary to trisomy X.
METHODS
A 16-year-old Japanese girl was diagnosed with childhood-onset systemic lupus erythematosus and trisomy X. A chromosomal abnormality (47, XXX) was incidentally identified on bone marrow examination initially done to determine the cause of pancytopenia. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Furthermore, thrombocytopenia, anemia, and erythrocyte fragmentation were detected, suggesting secondary thrombotic microangiopathy. She was initially treated with intravenous methylprednisolone pulse therapy and prescribed monthly cyclophosphamide for severe disease activity, prednisolone, mycophenolate mofetil, and hydroxychloroquine as remission maintenance drugs. She developed generalized extremity pain that had been worsening throughout the disease. Extremity magnetic resonance imaging performed 12 months after the treatment onset revealed multifocal avascular necrosis, and dual-energy X-ray absorptiometry revealed further decreased bone mineral density. High plasma levels of factor VIII were detected by additional tests for coagulation functions, and we suspected the possibility that factor VIII might cause avascular necrosis due to thrombosis. Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively even under the administration of non-steroidal anti-inflammatory drugs and pregabalin.
CONCLUSIONS
An additional X chromosome has been reported to be associated with factor VIII and osteoporosis. Additionally, elevated plasma levels of FVIII is the risk factors for thrombosis, which leads to the risk of avascular necrosis. Patients with systemic lupus erythematosus complicated by trisomy X might be at a higher risk of avascular necrosis and osteoporosis that can also manifest in childhood systemic lupus erythematosus.
Background
Systemic lupus erythematosus (SLE) is a multi-organ inflammatory autoimmune disease of unknown cause; immune complexes are part of the pathogenesis but not entirely responsible. If SLE develops before 18 years of age, it is classified as childhood-onset systemic lupus erythematosus (cSLE) [1]. Avascular necrosis (AVN) is a well-recognized complication of systemic lupus erythematosus (SLE), but the risk of AVN is usually lower in children than in adults. The prevalence of AVN in patients with SLE ranges between 10 % and 15 % [2]. Conversely, AVN prevalence in cSLE ranges between 5.4 % and 8.4 % [3–5].
The importance of the X chromosome in the pathogenesis of systemic lupus erythematosus (SLE) is well recognized, but its role in the development of bone complications remains unclear. Trisomy X is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births; most individuals are only mildly affected or asymptomatic [6]. The risk of SLE in Klinefelter’s syndrome is similar to that of normal females [7], and the prevalence of SLE in trisomy X is 2.5 times higher than in chromosomally normal females [8]. However, the studies of the clinical manifestations of SLE in trisomy/polysomy X have been scarce, and the bone complications have not been mentioned in any of them [9–11].
Herein, we report a case of cSLE in a female patient with trisomy X that developed severe bone complications.
Case presentation
The case described is of a 16-year-old Japanese girl who had no relevant family history. She had a medical history of attention deficit hyperactivity disorder (ADHD) and had been on atomoxetine since she was 12 years. She had developed stomatitis at the age of 12, alopecia at the age of 14, and butterfly erythema vulgaris at the age of 15. At the age of 16, she was referred to our hospital for suspected cSLE.
On physical examination at first presentation, the patient’s height and weight were 169.1 cm (+ 2.2 standard deviations above age average) and 44.2 kg, respectively; the tall stature was suggestive of trisomy X, but the associated facial features, such as epicanthal folds or hypertelorism, were not observed. She had a persistent headache, fever for six days, diffuse hair loss, mucosal ulcers, butterfly eruptions, and palmar erythema. Blood tests revealed pancytopenia (total white blood cell count: 3,400/µL; lymphocyte count: 958/µL; hemoglobin level: 7.9 g/dL; platelet count: 149,000/µL), In addition to thrombocytopenia and anemia, erythrocyte fragmentation (7.0 ‰; normal value: <1.2 ‰ [12]), elevated lactate dehydrogenase (355 IU/L), serum creatinine levels (0.91 mg/dL), low haptoglobin (< 10 mg/dL), and negative Coombs tests were observed, which were suggestive of secondary thrombotic microangiopathy(TMA); ADAMTS13 activity was normal. Concerning other SLE findings, low complement levels (C3: 25 mg/dL; C4: 2 mg/dL; CH50: 10 U/mL), and normal C-reactive protein levels (0.3 mg/dL) were revealed. The patient tested positive for the following autoantibodies: anti-nuclear antibody titer > 1:1280, homogeneous and speckled pattern; anti-DNA antibody 520 IU/mL; anti-double-stranded DNA antibody 1,010 IU/mL; anti-Smith antibody > 1:32; anti-U1 ribonucleoprotein antibody > 1:256. Tests for anti-SS-A antibody, anti-Scl-70 antibody, PR3-antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase-ANCA, anti-cardiolipin antibody (IgG), lupus anticoagulant, and anticardiolipin/beta2-glycoprotein I complex antibodies were negative. Urine analysis showed proteinuria (2.4 g/day), mixed cellular casts, and red blood cells; kidney biopsy was not performed, since urinary analysis results improved soon after treatment. Underlying infectious disease was ruled out by blood culture and whole-body computed tomography scan. To exclude malignancy due to pancytopenia, a bone marrow examination was performed. The result showed normocellular marrow and denied leukemia and myelodysplastic syndrome, but a chromosomal abnormality (47, XXX) was incidentally identified. Consequently, the patient was diagnosed with cSLE with trisomy X based on the American College of Rheumatology revised criteria [13], and was classified as having high disease activity, as the SLE disease activity index (SLEDAI) score was 27 [14]. There were two unusual findings for SLE. One was palladium calcification detected by the cranial magnetic resonance imaging (MRI) (Fig. 1a), and another was low bone mineral density detected by the dual-energy X-ray absorptiometry (DEXA) (lumbar spine: 0.972 g/cm2; Z-score − 1.7), which are commonly observed in the elderly.
Fig. 1 MRI (T2 weighted Image) findings were inconsistent with the patient’s age and revealed multiple sites of AVNSuspected calcification of the globus pallidus (a) and fatty changes in the lumbar spine (b: sagittal view), which are usually found in the elderly. AVN is seen in femoral head (c: axial view, d: coronal view); distal femur and proximal tibia (e: coronal view); distal tibia and talus (f: coronal view) AVN, avascular necrosis; MRI, magnetic resonance imaging
Due to high disease activity and suspected TMA complications, the patient chose a strong treatment method. The course of treatment is shown in Fig. 2. She was initially treated with two courses of intravenous methylprednisolone pulse therapy (1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days) with heparinization (150 IU/kg/day). Thereafter, monthly cyclophosphamide treatment was added (0.5 g/m2), and prednisolone was tapered. Alfacalcidol (0.5 µg/day) was administered from onset to prevent osteoporosis due to steroids’ side effects. Mycophenolate mofetil (MMF) (1500 mg/day) and hydroxychloroquine (200 mg/day) were added for the maintenance of remission, but were discontinued secondary to their adverse effects of leukopenia and alopecia, respectively; these symptoms abated after the withdrawal of these medications. Subsequently, belimumab was added as a remission maintenance drug, but no obvious effect was observed, and prednisolone dosage was increased up to 15 mg/day to control headache and elevated anti-dsDNA antibody. Generalized extremity pain developed early and worsened throughout the disease. Her visual analog scale of extremity pain score was always 9–10/10 even under administration of non-steroidal anti-inflammatory drugs, but differed from the doctor’s impression; because she could walk and bend knees naturally. Extremity MRI performed 6 months after the treatment onset was normal. However, a second MRI performed 6 months later revealed multifocal avascular necrosis (AVN) and the increased volume of adipose tissue in the bone marrow of the spine, similar to what is observed in the elderly [15] (Fig. 1b-f). Since the location of pain spread beyond the AVN position and unnaturally high visual analog scale score was persistent, it was determined that the causes of pain were attributable to a mixture of AVN and complex regional pain syndrome. Hence, pregabalin was added, but no effect was observed, and the pain persisted.
Fig. 2 Clinical course of the patient Black triangles show mPSL pulse (one course; mPSL 1 g/day for 3 days and maintenance therapy with prednisolone 1 mg/kg/day for 4 days). White triangles show monthly cyclophosphamide treatment 0.5 g/m2 (total six times). The first course of mycophenolate mofetil and hydroxychloroquine were discontinued owing to leukopenia and alopecia, respectively. From an early stage in the disease course, extremity pain had developed and worsened HCQ, hydroxychloroquine; IVCY, intravenous cyclophosphamide; MMF, mycophenolate mofetil; mPSL, methylprednisolone; PSL, prednisolone; SLEDAI, systemic lupus erythematosus disease activity index
Additional tests for coagulation defects were performed because one of the proposed mechanisms for vascular interruption in AVN is coagulation/ thrombus formation [4, 5]. Prothrombin time, activated partial prothrombin time, D-dimer levels, protein C and protein S activation, and antithrombin III activity were normal. However, the plasma levels of factor VIII (FVIII) and VWF antigen (VWF: Ag) were elevated (FVIII: 192.4 %, normal range 78–165 %; VWF: Ag > 201 %, normal range 50–150 %). These findings ruled out congenital thrombotic disorders such as protein C/S deficiency but revealed that the potential thrombotic condition might be caused by high levels of FVIII [16] and VWF: Ag [17]. Additionally, further deterioration and a mildly decreased bone mineral density were observed on the second DEXA (lumbar spine: 0.956 g/cm2; Z-score − 1.8). MMF was restarted for the concerns of ongoing deterioration, and rituximab was added to reduce steroid-related adverse effects, such as bone complications.
Currently, she is being treated with prednisolone and MMF for SLE. However, her extremity pain has not been managed effectively.
Discussion and conclusions
We have described a case of cSLE in a patient with trisomy X complicated by AVN and a decreased bone mineral density. In our patient, the development of these complications may have been related to an additional X chromosome.
It is possible that thrombosis due to interactions between FVIII encoded by the X chromosome and VFW might have caused AVN in our patient. Elevated plasma levels of FVIII [16] and VWF: Ag [17] are the risk factors for arterial and venous thrombosis, and a recent study suggested that their levels correlate [18]. Since the gene encoding FVIII is located on the long arm of the X chromosome [19], trisomy X patients might have possibly induced thrombosis due to the overexpression of FVIII. To support this hypothesis, the tendency for females to have higher levels of FVIII than males [20] might suggest an effect of the X chromosome on FVIII. In addition, a case of a severe leg ulcer in XXXXY syndrome due to elevated FVIII was previously reported [21]. A case-based review of SLE in female polysomy X reported that four out of five cases developed arthritis [9], which might be attributed to AVN. On the other hand, there was a report that FVIII levels increased even in Turner syndrome patients with portal vein thrombosis [22]. However, in that report, FVIII and VWF were not different between 25 Turner syndrome patients without thrombosis and 25 normal girls. Hence the high-level FVIII in Turner syndrome patients might be regarded as a consequence of just thrombosis, and not the dose of X chromosome.
Moreover, an additional X chromosome can elevate the risk for osteoporosis. Given that Klinefelter syndrome has been associated with an increased risk of osteoporosis [7], trisomy X may similarly follow suit. In addition, some trisomy X patients can develop premature ovarian failure, which is also a risk factor for osteoporosis [6]. Although our patient had not developed premature ovarian failure yet (progesterone and estradiol levels were normal), she already had a low bone mineral density before the start of the treatment, which might have reflected the characteristics of trisomy X. Since the use of corticosteroids is a well-known predisposing factor for osteoporosis [23], extra care should be taken when corticosteroid therapy is prescribed for the trisomy X patients compared to chromosomally normal females.
The hypothesis that an additional X chromosome might induce AVN due to thrombosis by overexpression of FVIII is derived by findings from only this single case, and this is our limitation. Of the 72 SLE patients, 32 had AVN, and 14 were reported to have multiple AVN in 4 or more locations [24]. In our report, although multiple AVN can be explained as just a potential complication of SLE, it would be rarely explained as cSLE in our experience. There were no reports of FVIII statistics in trisomy X; only one case report has reported this, as mentioned above [21]. Although not all trisomy X cases develop into thrombosis, and most are asymptomatic, in the case of SLE with trisomy X, we might need to be concerned about FVIII and bone complications.
In summary, it is important to consider the risk of AVN and osteoporosis in SLE patients with trisomy X more so than in chromosomally normal females, even in the case of a childhood onset.
All authors read and approved the final manuscript.
Abbreviations
SLESystemic lupus erythematosus
cSLEChildhood-onset systemic lupus erythematosus
PSLPrednisolone
AVNAvascular necrosis
ANCAAntineutrophil cytoplasmic antibody
MRIMagnetic resonance imaging
MMFMycophenolate mofetil
FVIIIFactor VIII
VWFAg Von Willebrand factor antigen
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Acknowledgements
We would like to thank the patient and the patient’s family for allowing this publication.
Authors’ contributions
SY planned and carried out the patients’ treatment and drafted the manuscript. SA, YA, and MM planned and carried out the patients’ treatment and helped draft the manuscript. SM, TN, and MM contributed the critical revisions of the manuscript for important intellectual content. The author(s) read and approved the final manuscript.
Funding
Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Nippon Kayaku Co., Ltd., UCB Japan Co. Ltd., and Asahikasei Pharmaceutical Corporation.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The report was conducted in adherence with the Declaration of Helsinki, and written informed consent was obtained from the patient and the patient’s guardians. IRB/Ethics Committee ruled that approval was not required for this study.
Consent for publication
Written informed consent was obtained from the patient and the patient’s guardians.
Competing interests
The authors declare that they have no competing interests. | 1500 MILLIGRAM, DAILY | DrugDosageText | CC BY | 33622323 | 19,076,387 | 2021-02-23 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | AZITHROMYCIN ANHYDROUS, CIPROFLOXACIN, CLARITHROMYCIN, CLOFAZIMINE, LINEZOLID, MEROPENEM, MOXIFLOXACIN, RIFABUTIN, TIGECYCLINE | DrugsGivenReaction | CC BY | 33622490 | 19,166,590 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | AZITHROMYCIN ANHYDROUS, CIPROFLOXACIN, CLARITHROMYCIN, CLOFAZIMINE, LINEZOLID, MEROPENEM, MOXIFLOXACIN, RIFABUTIN, TIGECYCLINE | DrugsGivenReaction | CC BY | 33622490 | 19,166,590 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy toxic'. | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | AMIKACIN, AZITHROMYCIN ANHYDROUS, BEDAQUILINE, CIPROFLOXACIN, CLOFAZIMINE, ETHAMBUTOL HYDROCHLORIDE, LINEZOLID, MEROPENEM, MOXIFLOXACIN, RIFABUTIN, TEDIZOLID, TIGECYCLINE | DrugsGivenReaction | CC BY | 33622490 | 19,188,929 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pathogen resistance'. | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | AZITHROMYCIN ANHYDROUS, CIPROFLOXACIN, CLARITHROMYCIN, CLOFAZIMINE, LINEZOLID, MEROPENEM, MOXIFLOXACIN, RIFABUTIN, TIGECYCLINE | DrugsGivenReaction | CC BY | 33622490 | 19,166,590 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | AMIKACIN, AZITHROMYCIN ANHYDROUS, BEDAQUILINE, CLOFAZIMINE, IMIPENEM, MOXIFLOXACIN, TIGECYCLINE | DrugsGivenReaction | CC BY | 33622490 | 19,096,291 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tinnitus'. | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | AMIKACIN, AZITHROMYCIN ANHYDROUS, BEDAQUILINE, CLOFAZIMINE, IMIPENEM, MOXIFLOXACIN, TIGECYCLINE | DrugsGivenReaction | CC BY | 33622490 | 19,096,291 | 2021-03 |
What was the administration route of drug 'AMIKACIN'? | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33622490 | 19,096,291 | 2021-03 |
What was the outcome of reaction 'Drug ineffective'? | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | Not recovered | ReactionOutcome | CC BY | 33622490 | 19,166,590 | 2021-03 |
What was the outcome of reaction 'Renal impairment'? | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | Recovered | ReactionOutcome | CC BY | 33622490 | 19,096,291 | 2021-03 |
What was the outcome of reaction 'Toxicity to various agents'? | Bedaquiline as Treatment for Disseminated Nontuberculous Mycobacteria Infection in 2 Patients Co-Infected with HIV.
Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.
Nontuberculous mycobacteria (NTM) cause a broad spectrum of disease, most commonly pulmonary infection, but also cause disseminated infection in immunocompromised patients, posing a major risk for illness and death (1). Treatment involves immune function optimization and prolonged use of combinations of species-specific antimycobacterial drugs but is often complicated by the intrinsic or acquired drug resistance of NTM (2) and adverse effects of the drug combinations; treatment failure is common. Therefore, there is considerable interest in the use of novel drugs (3).
Bedaquiline, a novel, oral, diarylquinolone antimycobacterial drug, is used in treatment of infections with multidrug-resistant Mycobacterium tuberculosis (4). However, its role in treatment of disseminated NTM infections remains unclear. We report the successful use of bedaquiline in treatment for 2 HIV-infected patients in London, UK, who had disseminated NTM infections.
The Study
Case-patient 1 was a 54-year-old HIV-infected man who had colonic perforation secondary to rectal trauma. He underwent an emergency Hartmann’s procedure and showed an uncomplicated immediate recovery. Two months later, he showed development of fevers, breathlessness, and a purulent exudate at the abdominal wound site, which did not improve after receiving antimicrobial drug therapy. Imaging showed pleural effusions and perihepatic collections; mycobacterial liquid culture of effusions, collections, and wound exudate contained M. abscessus, presumed secondary to fecal abdominal cavity contamination. Mycobacterial blood cultures were negative.
At diagnosis of his disseminated NTM infection, HIV viral load was undetectable (CD4 count >900 cells/μL). Empirical treatment was begun and then refined after speciation as M. abscessus (Figure 1, panel A). Susceptibility testing subsequently demonstrated extensive drug resistance (Table 1). MIC estimations for bedaquiline showed in vitro susceptibility (MIC <0.0625 mg/L). There was no information on Clinical and Laboratory Standards Institute/European Committee on Antimicrobial Susceptibility Testing for M. abscessus. The MIC breakpoint for this drug with M. tuberculosis was 0.25 mg/L (T. McHugh, University College London, pers. comm., 2020 Jun 29). Compassionate access to bedaquiline was obtained from Janssen-Cilag https://www.janssen.com). Treatment was initiated (400 mg/d for 2 wks, followed by 200 mg 3×/wk), as per treatment for tuberculosis. Bedaquiline was well tolerated and treatment continued for a year; there was a brief interruption because of a delay in reapproval.
Figure 1 Summary of treatment and monitoring of 2 HIV-positive persons who had disseminated Mycobacterium abscessus infections, London, UK. A) Case-patient 1. B) Case-patient 2. The infection in case-patient 1 was secondary to fecal abdominal cavity contamination after rectal perforation. Bars in top section show timing of treatments; red indicates bedaquiline. Drug regimens and treatment responses were measured by using Hb (g/L), Neut (× 109 cells/L), and CRP (mg/L). Values (+ and –) on the bottom of panel B are results for mycobacterial blood cultures. CRP, C-reactive protein; Hb, hemoglobin; Neut, neutrophils.
Table 1 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 1 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin Month 0: 16 Sensitive
Month 3: 32 Intermediate
Cefoxitin 128 Resistant
Ciprofloxacin >4 Resistant
Clarithromycin >16 Resistant (phenotype suggestive of inducible resistance)
Cotrimoxazole >8/152 Resistant
Doxycycline >16 Resistant
Imipenem 16 Intermediate
Linezolid Month 0: 32 Resistant
Month 3: 16 Intermediate
Moxifloxacin >8 Resistant
Tigecycline 2 No defined breakpoints
Tobramycin 8 Resistant
*MICs were obtained for the initial isolate of the patient at month 0, and again at month 3. Where duplicated, values were consistent, except for amikacin and linezolid, where both MICs are included. CLSI, Clinical and Laboratory Standards Institute.
During his treatment for NTM, the patient showed adverse effects caused by intravenous amikacin (1 g/d) and mild renal impairment. Therefore, this drug was withheld until his renal function recovered. On its reinitiation at the same dose, tinnitus developed prompting permanent withdrawal of amikacin. Because of excellent progress, tigecycline was replaced with linezolid at that time.
18Fluorodeoxyglucose-positron emission tomography/computed tomography imaging was used to monitor disease response (Figure 2). Although pulmonary and hepatic lesions emerged intermittently, they were consistently culture negative and are believed to represent immune-mediated lesions. His most recent scan 36 months after treatment began showed ongoing, but greatly reduced, 18fluorodeoxyglucose avidity in all areas. Therefore, he continues maintenance therapy with clofazimine and azithromycin, despite evidence of clarithromycin resistance in vitro. This combination (clofazimine and azithromycin) has been well tolerated, and the condition of the patient continues to be favorable.
Figure 2 Serial 18fluorodeoxyglucose-positron emission tomography/computed tomography imaging quantification of disease burden for an HIV-positive person (case-patient 1) given treatment for disseminated Mycobacterium abscessus infection, London, UK. Images demonstrate marked reduction in fluorodeoxyglucose avidity over time.
Case-patient 2 was a 30-year-old man who had pyrexia, pancytopenia, and lymphadenopathy. Advanced HIV infection had been diagnosed 1 month earlier (CD4 count 10 cells/μL, viral load >1 million copies/mL). He started antiretroviral therapy 10 days before he came to the hospital. Culture of lymph node, peripheral blood, and sputum all yielded M. avium. Treatment with azithromycin, rifabutin, and ciprofloxacin was initiated. Ethambutol was excluded because of color blindness.
The patient initially transferred his care to another hospital but returned 6 months later because of abdominal pain. Mycobacterial blood cultures had remained persistently positive throughout the intervening period, and at his return cultures of blood, bone marrow, and lymph node were positive for M. avium. We performed sensitivity testing (Table 2). Few drugs have MIC values for M. avium, and the correlation between MIC and clinical outcomes for drugs other than clarithromycin is unclear (5). The isolate demonstrated new clarithromycin resistance, postulated to have emerged because of persistence through treatment with a macrolide-containing regimen without ethambutol (6). His treatment was intensified by addition of amikacin and, after discussion with ophthalmologists, ethambutol. Because he continued to have fevers, meropenem, which covered the possibility of bacterial sepsis, and clofazimine were initiated, leading to symptomatic improvement. Because his symptoms worsened again on brief cessation of meropenem, it was continued.
Table 2 MICs and CLSI interpretation as reported by Public Health England reference laboratory for all drugs tested against Mycobacterium abscessus isolate from case-patient 2 (5)*
Drug MIC, mg/L CLSI interpretation
Amikacin intravenous >64 Resistant
Ciprofloxacin >16 No defined breakpoints
Clarithromycin Not reported Month 0: sensitive; month 6: high-level resistance
Doxycycline >16 No defined breakpoints
Ethambutol >16 No defined breakpoints
Linezolid 64 Resistant
Moxifloxacin >8 Resistant
Rifampin >8 No defined breakpoints
*MICs were calculated for the isolate at the initial presentation (month 0) of the patient and again at his representation 6 mo later. The second testing identified a new high level of resistance. CLSI, Clinical and Laboratory Standards Institute.
Treatment for this patient required multiple modifications because of adverse drug effects (Figure 1, panel B). Amikacin was stopped because of renal toxicity. Given the extensive in vitro resistance, best practice recommendation to add 2 drugs synchronously, lack of access to bedaquiline at this time, and evidence for a possible benefit of tigecycline in combination with a macrolide (7), tigecycline and linezolid were initiated in its place, causing nausea and anemia, respectively. He also had arthralgia secondary to moxifloxacin and QTc prolongation caused by azithromycin, which required their cessation.
Shortly after linezolid and azithromycin were discontinued his fevers and neutropenia returned. Mycobacterial blood cultures again showed M. avium despite prolonged treatment and immune reconstitution. Although bedaquiline sensitivity of this isolate was not determined in vitro, compassionate access to bedaquiline was obtained from Janssen-Cilag, and treatment was initiated at month 13 (dosing as reported for case-patient 1), along with tedizolid. Rifabutin was discontinued because of concerns over its effect on bedaquiline pharmacokinetics.
After bedaquiline and tedizolid were initiated, his fevers resolved, and he made a steady recovery and had no side effects. Given his high risk for relapse, he received bedaquiline for 18 months on the advice of the British Thoracic Society panel, ensuring a year of effective therapy since his last positive blood culture. He has successfully immune reconstituted, continues to receive only antiretroviral therapy, and remains healthy.
Conclusions
Treating disseminated NTM infections is challenging and often complicated by antimicrobial resistance and adverse effects of combination drug therapy. In multidrug-resistant M. tuberculosis, bedaquiline has been shown to decrease the time to sputum culture negativity and improve outcomes (8), leading to interest in its use for NTM infections.
In vitro sensitivity of NTM to bedaquiline has been demonstrated (9,10), although several species, including M. novocastrense, M. shimodei, and M. xenopi, are intrinsically resistant (11). In addition, although bedaquiline is bactericidal against many mycobacterial species, it might only be bacteriostatic against M. avium (12). Despite this feature, bedaquiline has been used in salvage treatment for pulmonary infections with NTM (13), but little experience regarding its use for disseminated NTM infections has been published.
These 2 case-patients were given bedaquiline on compassionate grounds, given the lack of alternative options because of drug resistance and toxicity. For both patients, bedaquiline enabled construction of an antimicrobial drug regimen that included >2 drugs to which the organism was susceptible in vitro and probably contributed to their positive outcomes. Both patients tolerated the drug and made good clinical progress after its initiation. Given the need for combination therapy, it is impossible to attribute the positive outcome of these cases to a single drug. Both patients received bedaquiline and clofazimine because there is evidence that this combination is synergistic against NTMs in vitro (14). Case-patient 2 only achieved sustained mycobacterial culture negativity after treatment with bedaquiline and tedizolid.
Use of bedaquiline as salvage therapy for pulmonary NTM infection is often complicated by the emergence of drug resistance and disease relapse (15). These case-patients received bedaquiline for >1 year, and neither showed evidence of the acquisition of drug resistance or disease relapse over that time or since. These case-patients provide support for use of bedaquiline for treatment of disseminated NTM infection, particularly when standard regimens cannot be used because of drug resistance or adverse drug effects.
Dr. Gil is an infectious diseases and microbiology registrar at the North Middlesex Hospital, London, UK. Her primary research interests are tissue immunology, leukocyte recruitment, and immune deficiency.
Suggested citation for this article: Gil E, Sweeney N, Barrett V, Morris-Jones S, Miller RF, Johnston VJ, et al.. Bedaquiline as treatment for disseminated nontuberculous Mycobacteria infection in 2 patients co-infected with HIV. Emerg Infect Dis. 2021 Mar [date cited]. https://doi.org/10.3201/eid2703.202359 | Recovered | ReactionOutcome | CC BY | 33622490 | 19,096,291 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Alanine aminotransferase increased'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aspartate aminotransferase increased'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epstein-Barr virus infection reactivation'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN\CLAVULANATE POTASSIUM, DIPHENHYDRAMINE, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,009,695 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatomegaly'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatotoxicity'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN\CLAVULANIC ACID, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Inappropriate schedule of product administration'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN\CLAVULANATE POTASSIUM, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,054,231 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product misuse'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN\CLAVULANIC ACID, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy toxic'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN\CLAVULANIC ACID, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | AMOXICILLIN, MINOCYCLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
What was the administration route of drug 'AMOXICILLIN\CLAVULANIC ACID'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
What was the administration route of drug 'MINOCYCLINE HYDROCHLORIDE'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
What was the dosage of drug 'MINOCYCLINE HYDROCHLORIDE'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
What was the outcome of reaction 'Alanine aminotransferase increased'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
What was the outcome of reaction 'Aspartate aminotransferase increased'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,047,119 | 2021-02-24 |
What was the outcome of reaction 'Drug reaction with eosinophilia and systemic symptoms'? | Complicated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome History in a 14-Year-Old.
BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction that can result in a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs after exposure to sulfonamides, antibiotics, or antiepileptics. Its incidence in children is not established; however, the mortality rate is documented at approximately 10%. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses including EBV and HHV-6. The classic presentation includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. CASE REPORT We present a unique case of DRESS syndrome in a 14-year-old girl occurring after the ingestion of minocycline and amoxicillin-clavulanic acid (amoxicillin). Identification of the offending agent was complicated by the patient having been on multiple antibiotics within a short timeframe of the initial presentation of symptoms. In addition to swelling and pruritus, the patient experienced vision problems due to papilledema with bilateral hemorrhage. The treatment course was further complicated by a decrease in kidney function, requiring the patient's medication regimen to be adjusted accordingly. CONCLUSIONS This is a unique case of DRESS syndrome demonstrating the potential influence of certain viruses on the severity of its presentation. This case also highlights the need to adjust the steroid regimen to reduce the potentially harmful effects on various organ systems.
Background
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is classified as a drug-induced hypersensitivity reaction, as well as a severe cutaneous adverse drug reaction (SCAR). It is a rare and potentially life-threatening condition that occurs primarily after exposure to antibiotics, particularly sulfonamides, or antiepileptics [1,2]. Its incidence in children is not established; however, its mortality rate is documented at approximately 10% [3]. DRESS syndrome is believed to result from an interaction between multiple factors, including genetics, abnormalities of metabolism, and reactivation of certain herpes family viruses, including human herpes virus (HHV)-6, HHV-7, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) [4].
The classic presentation of DRESS syndrome includes fever, rash, and lymphadenopathy. Symptoms begin approximately 3 to 8 weeks after exposure to the offending agent. Facial edema, which is considered as the hallmark feature of the disease, is present in approximately 76% of cases [5]. Typically, the liver and kidney are affected, but other organs potentially involved are the pancreas, thyroid, heart, brain, muscle, peripheral nerves, and eye [6].
In this case report, we present a unique case of DRESS syndrome occurring after the ingestion of amoxicillin and minocycline. This report highlights the need for proper detail-oriented history taking, necessity of close follow-up, with special attention to the monitoring of renal function, and adaptations in the scheduling of steroid tapering.
Case Report
The patient is a 14-year-old Black girl in generally good health, who presented with a sore throat and a diffuse pruritic rash over her entire body, which started 6 days prior to presentation. The history that was gathered from the Emergency Department (ED) visit was complex and required extensive questioning to understand the sequence of events that may have led to her symptoms. The patient presented to our ED with rash and swelling of the face and arms (Figure 1). Prior to presentation to our ED, the patient had sought care at multiple urgent care clinics and EDs. Approximately 14 to 30 days prior to arrival, the patient was prescribed minocycline by a dermatologist. The exact date the medication was started is unknown and was unable to be confirmed. Approximately 2 weeks later, the patient went to a water park, after which she experienced symptoms of suspected ear infection. The patient self-medicated with an old bottle of amoxicillin for about 1 week, with inconsistent frequency. Nonetheless, the symptoms persisted. She visited an urgent care clinic and was prescribed amoxicillin for a suspected sinus infection. A rash occurred after the first prescribed dose of amoxicillin. Due to the nonspecific reported timeline of the patient’s initial incomplete course of amoxicillin, the patient’s timeline (Day 1) begins at presentation, the day she took her first dose of prescribed amoxicillin and the rash initially developed. The patient went on to complete 3 total doses of amoxicillin at this time (Table 1).
The rash was described as erythematous, with fine papules all over her body. The face and arms were more affected than the rest of the body. The rash was reported to have developed cranio-caudally. The patient’s eyelids then became swollen bilaterally, with generalized face swelling. The patient stopped taking amoxicillin after the third dose, but the rash progressed, and significant itching developed.
Six days later (Day 7), the patient sought care at an ED because of persistent itching. She was discharged home with diphenhydramine. The pruritic rash persisted, and throat swelling developed. Since her symptoms did not improve, the patient returned to the ED the next day (Day 8). She noted an increase in a diffuse erythematous papular rash all over her body. Furthermore, the patient reported minor visual changes, which she described as blurry vision and some dizziness.
At this time the patient was given steroids (Decadron, PO, reported as standard dosing) and epinephrine IM, and was admitted for overnight observation. Her laboratory test results showed alanine aminotransferase (ALT) of 70 units/L and aspartate aminotransferase (AST) of 62 units/L (upper limit normal, 55 and 40 units/L, respectively). She was discharged the next day (Day 9) with diphenhydramine and prednisone 20 mg PO to take twice per day (bid). The patient followed this regimen for 3 days without an improvement in the swelling, rash, and itchiness.
At this time (Day 12), the patient presented to our institution’s ED with a pruritic, erythematous rash, and was noted to have periorbital edema. On physical examination, all body systems were otherwise normal. Initial laboratory results were significant for the complete blood count showing leukocytosis (an elevated white blood cell [WBC] count) of 38.5 k/μl, and a manual differential with an eosinophil count of 18%. The patient received IV fluids, diphenhydramine, and methylprednisolone 40 mg IV every 12 h. She was admitted for further monitoring.
Treatment with hydroxyzine was started on Day 13. This regimen of medications continued for 3 days, and the patient was discharged home on Day 16. During the hospitalization, repeat testing of eosinophils on a manual differential were noted to be 15%. The patient was provided instructions to taper the dose of steroids at home. The day following discharge (Day 17), the patient reported a fever of 39.1°C and an episode of non-bloody, non-bilious vomiting. She went to her primary doctor the next day (Day 18) complaining of a sore throat, fever, cough, and blurry vision. Although her visual symptoms had improved initially, the patient experienced a worsening in visual acuity and mild associated dizziness. She was prescribed azithromycin and albuterol. Laboratory results were significant for an elevated WBC of 35 k/μL.
Two days after seeing her primary doctor (Day 20, 4 days after discharge from our hospital) the patient returned to our ED with a fever of 38.7°C, dizziness, submental and submandibular lymphadenopathy, and generalized maculopapular rash of the arms, legs, torso, and back. She received a stress dose of 1 g of methylprednisolone and was admitted to the hospital.
Magnetic resonance imaging (MRI) of the brain and electrocardiogram results were unremarkable. Ultrasound imaging showed hepatomegaly. The patient’s liver function test (LFT) results were significantly elevated, with ALT 1080 units/L and AST 1836 units/L. The renal function test results showed a BUN level of 15 mg/dL and a creatinine level of 2.22 mg/dL. Thus, the patient was admitted to the Pediatric Intensive Care Unit. Upon admission, the patient’s laboratory test results were significant for leukocytosis (WBC 32.1 K/uL) and prominent eosinophilia (eosinophils 18%) on the manual differential, which was consistent with DRESS syndrome. The EBV titers were measured at IgM <36 U/mL and IgG 526 U/100 mL; the IgM titer was within normal limits at this time. The patient received IV methylprednisolone 1 g every 24 h for 3 days (finishing on Day 23). During this time, the patient’s LFTs and creatinine levels were noted to be significantly elevated, but they later normalized after the 3 days of IV steroid administration (Table 1).
The patient clinically improved, and was discharged from the hospital (Day 24) with oral prednisone 25 mg bid after a 4-day admission. The patient’s prednisone dosage was increased to 30 mg bid the next day (Day 25) because of ongoing symptoms. Throughout the following week, her laboratory values were monitored closely on an outpatient basis, with specific attention paid to her renal function. The patient’s creatinine level was noted to increase from 1.28 mg/dL to 1.61 mg/dL (Table 1), which prompted a multiple-day course of outpatient IV steroid infusion treatment. The patient received a daily dose of IV solumedrol for 4 days (Day 33 to Day 36). Similar to the results from her previous IV steroid treatment, there was dramatic improvement in her creatinine, with levels that decreased from 1.61 mg/dL to 1.33 mg/dL, and then to 0.86 mg/dL, with restarting of oral prednisone treatment of 30 mg bid (Table 1).
One week later (Day 43), the patient returned with complaints of significant blurry vision. At an outpatient ophthalmology clinic, she was found to have papilledema with bilateral hemorrhage. The patient went to the ED and was readmitted to the hospital, approximately 1 month after her initial admission.
The 2 competing diagnoses at this time were pseudotumor cerebri, secondary to high-dose steroids, and ongoing DRESS syndrome. The patient’s MRI scan was unremarkable. The EBV titers were repeated and showed IgM >100 mg/dL, which was significant and added to the complicated nature of this case, as it indicates a possible reactivation of EBV, as compared with the previous levels of IgM of 36 U/mL. The patient underwent a lumbar puncture with an increased opening pressure of 40 cm H20. The results from all other studies were unremarkable. The patient was treated with acetazolamide, which led to an improvement of symptoms, and the patient was discharged after 4 days.
The patient’s dosage of oral prednisone was decreased to 20 mg bid, and while her creatinine had a brief increase to 1.19 mg/dL, it consistently decreased afterward (Figures 2–4). The ongoing concern of autoimmunity was continually followed up and only nonspecific antinuclear antibodies (ANA) were found to be elevated, with a 1: 1086 titer. All other titers and values were noted to be negative, indicating no significant concern of an additional developing autoimmunity.
The patient was transferred to the affiliated academic medical center. Consultations with the Departments of Neurology, Ophthalmology, Nephrology, Rheumatology, and Dermatology confirmed the DRESS diagnosis. The rheumatology specialist repeated all titers, including histone AB, and only ANA was elevated, once again. The patient continued on prednisone 20 mg bid for fluctuating renal function indicators. On a repeat ophthalmology examination, papilledema was still present but was noted to have continually improved after the patient began treatment with acetazolamide. No other visual field deficits were noted at the time. The patient’s renal function continued to steadily improve. Finally, the patient was discharged after a 10-day admission at the affiliated academic medical center (Day 54). The ophthalmologist agreed that the patient should continue taking prednisone, with slow tapering.
Although the protocol [7] recommended decreasing the prednisone dosage by 5 mg per week and checking weekly laboratory examination results, it was decided to maintain a total daily dosage of 40 mg, owing to the repeat elevation in the patient’s creatinine values. Two days after discharge (Day 56) the patient’s creatinine level was 0.98 mg/dL, indicating a significant improvement in her renal function. The patient was administered mycophenolic acid for 3 days (completed on Day 59). The administration of cyclosporine and cyclophosphamide was considered, but was refused by the patient due to concerns of the effects on her kidneys and fertility. The patient’s rash significantly improved after 2 months of treatment. The patient is still being followed by various specialists including, but not limited to, rheumatologists, neurologists, and nephrologists, and she continues to show clinical improvement.
The diagnosis of DRESS syndrome was considered early in the patient’s initial hospital course; however, due to an inaccurate reported history regarding the supposed timing of antibiotic consumption, it was not considered to be the main differential diagnosis. Upon further questioning during the worsening of symptoms, the patient remembered consuming medication 21 days prior to her initial presentation for a suspected ear infection. It was discovered that the medication was amoxicillin. To complicate matters further, the patient’s mother recalled that she was also prescribed minocycline by a dermatologist weeks before the initial symptoms began. This information greatly helped our team formulate a more effective treatment plan. A visual representation of the entire timeline is shown in Table 1.
Discussion
We present a unique case of DRESS syndrome for which we propose further emphasis on the monitoring of renal function throughout the course of the patient’s illness. For the most part, DRESS syndrome has been studied in the acute phase, with particular attention paid to the monitoring of LFTs [8].
It is uncertain which drug caused the drug reaction and DRESS syndrome in this particular case. The unknown timing and duration of the minocycline prevents us from ruling out that this is the culprit drug responsible for our patient’s symptoms, as hepatotoxicity, nephrotoxicity, eosinophilia, and DRESS have all been reported as adverse effects of minocycline [9]. It is also possible that amoxicillin led to the DRESS syndrome, perhaps in part due to the short timeframe of repeated doses [10]. We emphasize the necessity for proper history taking and discussion to show that the proper diagnosis may not have been achieved were it not for the realization of the potential reaction-causing drugs.
The current literature consistently states that DRESS syndrome is typically caused by antiepileptic medications [11], but practitioners should be aware of a severe reaction after the administration of antibiotics. This case emphasizes that causative agents of DRESS syndrome can also be antibiotic therapy, and not necessarily long-term antibiotic therapy. It was confirmed by our team of specialists that the patient in this case met all the necessary criteria to confirm the diagnosis of DRESS syndrome, as she met both DRESS/DIHS30 and DRESS RegiSCAR criteria for diagnosis [12] (Tables 2, 3).
An additional point of interest in our case is the patient’s age and demographic. Although the patient was of age to be prescribed minocycline, this was her first exposure to this medication. Mori et al showed that Blacks are most likely to develop DRESS syndrome after the initiation of aromatic anticonvulsants drugs, whereas Han Chinese are most likely to develop DRESS after allopurinol intake [3]. Our patient was an adolescent Black female who developed DRESS syndrome after antibiotic therapy, illustrating that further study is necessary to show the possible genetic predisposition to specific adverse drug effects.
A few viruses have been shown to be involved in drug hyper-sensitivity reactions and DRESS syndrome. The typical viruses include EBV and HHV6 [13]. In our patient’s case, HHV6 testing was unable to be conducted due to multiple samples of an insufficient quantity, but she was shown to have high EBV titers on multiple occasions. Remarkably, the patient had a reactivation of EBV; the patient’s EBV titer from her initial admission showed IgM 36 U/mL and IgG 496 U/mL, with a subsequent increase and a positive EBV IgM 50.8 U/mL and IgG 750.00 U/ mL 1 month later. These results are unusual because both EBV IgM and IgG levels were low initially and later increased; however, this has been shown in previous literature [4] and displays the importance of testing EBV (and HHV-6) titers on patients with suspected or confirmed DRESS syndrome.
Multiple case reports and medical journals state that the long-term prognosis and risk of mortality is mostly associated with LFTs [8]. The peculiar aspect of this case is that her clinical symptoms consistently coincided with her renal function. As her creatinine levels decreased and renal function improved after various steroid treatments, her clinical symptoms concurrently improved. This could indicate that renal function, specifically creatinine levels, could serve as a marker for severity of illness in DRESS syndrome. The administration of IV steroids had the most pronounced effect, resulting in the significant improvement of our patient’s LFTs, renal function, and clinical manifestations. The use of steroids as a treatment for DRESS syndrome needs to be specifically investigated to help establish a proper protocol. Using creatinine as a marker for ongoing steroid therapy is introduced as a novel concept in this case study. This can also potentially help to direct the dose adjustments and timing of the steroid taper. Of note, no further immunomodulatory therapy was used, as the patient’s symptoms continued to improve. Intravenous immunoglobulin (IVIG) was considered early on but was not given because the patient showed a response to steroids. The use of IVIG is considered anecdotal in nature, and a few studies show that not only is not very beneficial, but that it may in fact be associated with severe adverse effects [14].
Conclusions
There are numerous causes of DRESS syndrome, such as the reaction to specific medication, viral interference, and genetic predisposition. These range from a sole reaction to a particular medication to reaction to a combination of medications and the reactivation of certain viruses [5,13]. There is evidence of genetic predisposition and lack of metabolizing enzymes for these drugs, which cannot be ruled out in the present case [5]. DRESS diagnosis is further complicated because its symptoms overlap with many autoimmune diseases [15,16]. This specific case was complicated by the patient possibly having a reaction to either minocycline or amoxicillin [9,10]. The reaction could have also been due to repeat/prolonged exposure to amoxicillin [9]. Given the patient’s ethnicity, it is possible the reaction was caused by minocycline, which is common in those of Caribbean descent [9,17]. The present case is unique, as this is a rare presentation in a patient of this age and race/ethnicity [18]. The young age of the patient also lends an opportunity to potentially add to the knowledge of long-term effects of DRESS syndrome [3]. Due to the complexity of DRESS syndrome’s etiology and diagnosis, the utmost caution is needed with short-term and long-term management and the monitoring of a patient’s care. Outlining the most effective immediate treatment must include monitoring of both the liver and kidney functions to reduce potential adverse effects on the renal and hepatic systems. Long-term follow-up is needed to monitor for early development of any potentially related comorbidities, such as autoimmune disease.
Additional therapies, such as IVIG, require further research to better understand their utility in the treatment of DRESS syndrome.
Conflicts of Interest
None.
Figure 1. Erythematous papules visible on the patient’s arms.
Figure 2. The fluctuation of liver enzymes during the patient’s hospitalization period.
Figure 3. The fluctuation of BUN levels during the patient’s hospitalization period.
Figure 4. The fluctuation of creatinine levels during the patient’s hospitalization period.
Table 1. Patient timeline.The timeline displays the patient’s course starting from initial ingestion of the potential DRESS syndrome-inducing medications and subsequent reactions leading to the patient’s symptoms, laboratory values, and steroid treatment regimen are documented to show the patient’s course of illness and dosing of medications with subsequent steroid tapering.
Table 2. Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria.
1. Prolonged clinical symptoms 2 weeks after discontinuation of a medication
2. Maculopapular rash
3. Fever >38°C
4. Enlarged LN
5. Involvement of at least 1 internal organ (with ALT >100)
6. Eosinophilia (>1.5)
7. Leukocytosis
Table 3. Drug-induced hypersensitivity syndrome (DIHS)30 criteria.
1. Maculopapular rash developing >3 weeks after starting with the suspected drug
2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug
3. Fever >38.0
4. Liver abnormalities (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities
6. Leukocytosis (>11×109/L)
7. Atypical lymphocytosis (>5%)
8. Eosinophilia (>1.5×109/L)
9. Lymphadenopathy
10. Human Herpes 6 reactivation | Recovering | ReactionOutcome | CC BY-NC-ND | 33622999 | 19,053,028 | 2021-02-24 |
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