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What was the dosage of drug 'NITAZOXANIDE'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | UNK, DOSE INCREASED | DrugDosageText | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
What was the dosage of drug 'ZIDOVUDINE'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | UNK, SECOND-LINE THERAPY | DrugDosageText | CC BY-NC | 33732476 | 19,903,764 | 2021-03 |
What was the outcome of reaction 'Blood electrolytes abnormal'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Cachexia'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Condition aggravated'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Cryptosporidiosis infection'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Cytomegalovirus oesophagitis'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Dehydration'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Erythema'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Ichthyosis'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Oesophageal candidiasis'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Oral candidiasis'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Oral mucosal erythema'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Punctate keratitis'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'SJS-TEN overlap'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Skin lesion'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 19,889,986 | 2021-03 |
What was the outcome of reaction 'Stevens-Johnson syndrome'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 20,020,604 | 2021-03 |
What was the outcome of reaction 'Toxic epidermal necrolysis'? | Human immunodeficiency virus infection with multiple opportunistic infections: lessons learnt from a non-adherent patient.
We report a case of advanced human immunodeficiency virus (HIV) infection with multiple opportunistic infections (Pneumocystis carinii pneumonia, cryptosporidiosis, oesophagal candidiasis and cytomegalovirus infection). The patient was presumed to be adherent on antiretroviral therapy (ART) and was initiated on respective treatments for the opportunistic infections but continued to deteriorate. On further reviewing, he was found to be poorly adherent to ART and was advised enhanced adherence counselling after which his condition improved. We report this case to emphasize the importance of adherence to ART medications in the management of patients with HIV.
INTRODUCTION
Patients with advanced human immunodeficiency virus (HIV) infection have high morbidity and mortality owing to increased susceptibility to opportunistic infections. Early diagnosis and initiation of antiretroviral therapy (ART) is the cornerstone of management in patients with advanced HIV. Although a lot of stress is laid on the initiation of therapy, monitoring of compliance and importance of adherence in management is often neglected. We present a case of advanced HIV with multiple opportunistic infections to emphasize that adherence to ART is the most effective tool in managing patients with advanced HIV, and poor treatment adherence is associated with adverse outcomes.
CASE REPORT
A 50-year-old gentleman who worked in the para-military forces presented to a secondary care hospital with intermittent high-grade fever associated with loss of appetite and weight (around 10 kg) for a year. He was found to be positive for HIV-1 infection and was advised ART. He did not initiate ART and presented 2 months later to us with fever, shortness of breath and loose stools for 15 days. He was found to have a CD4 count of 62/mcl. A chest X-ray and computed tomography of the chest was done for these complaints, which was suggestive of Pneumocystis carinii pneumonia. He was managed in the intensive care unit with intravenous trimethoprim-sulfamethoxazole and steroids. After 2 days of initiation of treatment, he developed erythema over forearm, neck, chest and extremities. This was accompanied by oral mucosal involvement and punctate keratopathy. He was diagnosed as Steven Johnson syndrome-toxic epidemo-necrolysis overlap secondary to trimethoprim-sulfamethoxazole, which was immediately stopped, and he was put on steroids. His lesions resolved in next 2 weeks and he was started on tenofovir-disoproxil fumarate, lamivudine and efavirenz along with dapsone prophylaxis. ART was not started earlier as both tenofovir and efavirenz could have worsened the skin condition. He was discharged in a stable condition. He reported proper compliance in all his out-patient visits. Eighteen months into the illness, he started to have dysphagia and small bowel type of diarrhoea (15–20 times/day, non-bloody, not associated with abdominal pain and tenesmus) for which he was admitted. On upper gastrointestinal (UGI) endoscopy, he was found to have oesophagal candidiasis and was started on fluconazole. Stool microscopy revealed Cryptosporidium oocysts, and he was initiated on nitazoxanide. However, he continued to have diarrhoea with multiple stool samples detecting Cryptosporidium oocysts and had persistent dyselectrolytemia for which oral supplementation was given. He continued to deteriorate and was found to have features of dehydration, severe wasting, candidiasis (oral) and diffuse ichthyosis on examination. Dosage of nitazoxanide was increased, and azithromycin was added once daily for cryptosporidiosis to which he responded partially.
His CD4 count was zero, and viral load was high. His previous CD4 counts done at six-monthly intervals after the baseline count of CD4 of 62/mcl were 104/mcl and 76/mcl. With suspicion of failure, he was started on zidovudine, lamivudine and atazanavir/ritonavir. Single-tablet regimen with a protease inhibitor (PI) or integrase inhibitor was not available under the national scheme for use in this patient. HIV resistance genotyping did not detect any resistance to any of the tested drugs. On reviewing the history, he reported decreased adherence to the ART medications as he avoided taking his medications in front of his co-workers on outstation postings. He also seemed to be extremely worried about his ill health. He was counselled about the severity of his condition and the importance of adherence. He was referred to a trained psychologist for evaluation. He was found to be depressed and was started on anti-depressant by the psychiatrist. He was continued on a PI-based therapy, owing to its higher barrier to resistance, considering his history of non-compliance.
He continued to have persistent diarrhoea along with dysphagia not responding to fluconazole. Cytomegalovirus (CMV) esophagitis was suspected in addition to candidiasis based on raised CMV viral load and UGI endoscopy findings. He was started on valganciclovir after which his CMV viral load became negative. His diarrhoea and dysphagia eventually improved and was discharged on PI-based ART, dapsone prophylaxis and fluconazole. He was also registered for regular follow-up with the psychologist and psychiatrist.
DISCUSSION
Cryptosporidiosis is commonly seen in patients with advanced HIV with an overall prevalence of 8.7%. These patients present with a diarrheal illness which may last for months resulting in weight loss, malnutrition and extended hospitalization [1]. Although nitazoxanide is approved for the treatment of cryptosporidiosis, it is often ineffective. Other agents like azithromycin and PIs have been tried with minimal success. Effective ART is probably the most effective tool in managing patients with cryptosporidiosis [2].
CMV infection is associated with rapid HIV disease progression and consequently, more acquired immune deficiency syndrome related events. ART is not only effective in controlling HIV replication but also decreases CMV-related adverse events by the restoration of CMV-specific immunity [3]. CMV-related gastrointestinal disease is seen in HIV-infected patients with advanced immunosuppression. Oesophagus and colon are the most important sites that are affected [4]. Ganciclovir/valganciclovir, along with the initiation of effective ART, is the treatment of choice.
India has a total of >2 million HIV-positive individuals [5]. Most of these patients are managed in ART centres linked to the national programme. The national programme was initiated in 1992, and it has been giving free ART to all HIV registered HIV patients since 2004 [5]. The programme continues to give free ART to all the registered patients despite the decrease in its funding. The national programme has tried to keep up with the recommendations on the treatment given by the World Health Organisation. Since 2013, the first-line treatment has been a single-tablet regimen of tenofovir, lamivudine and efavirenz [5]. For those who fail the first-line treatment, they are shifted to a two-pill regimen containing atazanavir/ritonavir. While the programme works fairly well for most patients, in this patient, there were certain challenges. At the time, the patient presented routine viral load monitoring was not available for all patients at the centre. It was done only for those patients where immunological failure was suspected. Despite access to free ART, the number of centres that dispense medications is limited, leading to high patient turn over in each centre. Due to the high patient turn, the time spent with each patient is suboptimal, leading to a poor patient–physician relationship. Also, adherence is measured by pill counting method and therefore, it is easy to miss non-compliance. Single-tablet regimen with dolutegravir has been recently introduced in the national scheme, but it was not available at the time, the patient was being managed.
Variable drug adherence was noted (47–90%) in the studies from Indian centres [6]. The problem of drug adherence is further compounded by high pill burden, poor health literacy and treatment-related side effects in patients with HIV [7]. Poor treatment adherence to ART is associated with inadequate viral suppression, increased resistance and increased opportunistic infections [7–9]. It is essential to spend time with the patient and understand his/her problems during the initiation of ART. Patients are often scared of revealing their medical condition to their employers for fear of being judged and losing their job. It is also essential to empowering the patient about their rights [8,9]. Poor treatment adherence to ART, due to various socio-economic factors, is often missed by healthcare staffs [10]. It is imperative to consider the social aspects like living conditions, economic support, working conditions and family support.
Potential solutions to improve adherence include better education and motivation of patients, early referral for diagnosis and treatment, home visits, an increase in human resources and, creating social support groups. Patient education programmes are essential not only in the hospital but also in the communities near patients’ residence. This would help to dispel the misconceptions and stigma associated with HIV infection. Adherence counselling, although a time-consuming process is an advantageous intervention in terms of overall patient outcome.
ACKNOWLEDGEMENTS
Nil.
CONFLICT OF INTEREST STATEMENT
None declared.
FUNDING
None to declare.
ETHICAL APPROVAL
Not applicable.
Consent was taken prior to publications.
Guarantor—same as the corresponding author. | Recovered | ReactionOutcome | CC BY-NC | 33732476 | 20,020,604 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiogenic shock'. | Cardiac arrest in anti-mitochondrial antibody associated inflammatory myopathy.
Insight into predictors of cardiac involvement in inflammatory myopathies is sparse. A negative prognostic role of anti-mitochondrial antibodies (AMA) has been noticed and is supported by the current case. We describe a male patient who at the age 40 suffered a cardiac arrest and over the following months experienced progressive heart failure, arrhythmias and proximal muscle weakness. Clinical, genetic and serologic testing and repeated imaging- and histopathological investigations resulted in a diagnosis of AMA-associated, necrotizing, inflammatory myositis with cardiac involvement. Besides a cardiac resynchronization therapy defibrillator, heart failure and antiarrhythmic drugs the patient received successive immunosuppressants, which improved skeletal muscle strength but not cardiac disease progression. At age 45 he died from end-stage heart failure. Clinicians must be aware of AMA-associated myositis as a cause of unclarified heart disease, even in patients with initially sparse extra-cardiac manifestations. Further knowledge of treatment strategies is highly needed for this disease entity.
INTRODUCTION
Inflammatory myopathy is a heterogeneous disease entity affecting primarily the skeletal muscles. Anti-mitochondrial antibodies (AMA)—the serological hallmark of primary biliary cholangitis (PBC)—exist in a subgroup of myositis patients and may predict serious cardiac involvement [1, 2]. Awareness of AMA and their pathophysiological role in myositis is of great therapeutic and prognostic relevance as illustrated by this case.
Figure 1 Electrocardiogram after resuscitation for cardiac arrest showing atrial fibrillation, ventricular extra systoles and q-waves along the anterior leads.
Figure 2 Cardiac magnetic resonance imaging (CMRI). Late gadolinium enhancement images in the short axis (a), and four chamber (b) of the heart. The arrows point to the pathologic area of the myocardium (white area in the background of normal, black, myocardium).
Figure 3 Serological disease activity markers including levels of Troponin-I (TN-I), pro B-type Natriuretic Peptide (pro-BNP) and total Creatine Kinase (CK) over time and in relation to the clinical course and treatment with Prednisolone (Pred.)/*methylprednisolone, Methotrexate (MTX), Ciclosporin (Cicl.), Mycophenolate mofetil (Mmf) and Rituximab (Rtx).
Figure 4 Cardiac PET-CT with F-18-FDG/Rb-82 revealing nonviable perfusion defect in the apex and the lateral wall of the left ventricle (arrows).
Figure 5 Histopathological images of myocardial biopsy showing (a, HE) mild to moderate hypertrophy and replacement fibrosis (arrow) with endothelial proliferation, few inflammatory cells and (b, AVG) alcian-positivity (arrow).
CASE REPORT
A 40-year-old male with a medical history of Graves’ disease and paroxysmal atrial flutter (PAF) was admitted to the hospital on February 2016 after resuscitation for cardiac arrest/ventricular fibrillation (VF). He had no risk factors for ischemic heart disease. At arrival to the hospital, the electrocardiogram showed atrial fibrillation, ventricular extra systoles and q-waves in anterior leads (Fig. 1). In hospital heart monitoring showed paroxysmal complete heart block. Blood tests revealed elevated troponin-T (262, [<14 ng/L]), creatine kinase (CK) myocardial band (46,1 [<7 μg/L]) and total CK (2530 [25–400 U/l]). Chest X-ray showed cardiomegaly, and transthoracic echocardiography (TTE) disclosed dilatation of left ventricle with ejection fractions (LVEF) of 25–30%, hypofunction of right ventricle and inferoseptal akinesia. Coronary angiography (CAG) showed normal coronary arteries. Cardiac magnetic resonance imaging (CMRI) confirmed inferoseptal akinesia of the distal part of the myocardium in the left ventricle where late gadolinium enhancement (LGE) was found in a subendocardial, almost transmural pattern (Fig. 2a and b). A Cardiac-Resynchronization-Therapy-Defibrillator device (CRT-D) was implanted, and anticoagulants, antiarrhythmics, statin and heart failure therapy were started. The patient complained of muscle weakness for 2 years. Medical records showed elevated total CK (2000–3000 U/l) tracing back to 2014. Muscle strength testing confirmed proximal weakness of all extremities but no other signs of rheumatic/neurologic disease. The patient was subsequently followed by both cardiologists and neurologists, where progressive muscular weakness, repetitive supraventricular and ventricular arrhythmias and elevated cardiac/muscle enzymes were registered between 2016 and 2017 (Fig. 3). Serological tests for myositis-specific autoantibodies (MSAs) including anti-HMGCR, ANA and genetics for neuromuscular diseases were negative. Whole-body positron-emission-tomography computed-tomography (PET-CT) and pulmonary function tests were normal. Muscle biopsy showed fiber variability and cell necrosis compatible with immune-mediated, necrotizing myopathy. Prednisolone (75 mg/day) was initiated in January 2018 resulting in improved physical performance. In March 2018 methotrexate (MTX) (15–25 mg/week) was added and prednisolone tapered, resulting in continued clinical improvement and stable LVEF of 35%. In March 2019, while treated with MTX (20 mg/week) monotherapy, the patient experienced worsening of muscle weakness and dyspnea. Blood tests showed rising total CK (Fig. 3) and X-ray revealed pulmonary congestion. The condition improved transitorily on diuretics and increased MTX (25 mg/week). Six months later, the patient was brought to intensive care in cardiogenic shock due to decompensated severe biventricular failure. He was stabilized by inotropic support, diuretics, amiodarone, upregulation of CRT pace and glucocorticoids. TTE depicted biventricular hypofunction/dilatation (LVEF 10–15%), and a cardiac PET-CT (F-18-FDG/Rb-82) showed nonviable perfusion defect in the apex and lateral wall of the left ventricle (Fig. 4). A myocardial biopsy revealed mild to moderate hypertrophy and maturing replacement fibrosis with alcian-positive matrix indicating the presence of glycosaminoglycans as seen in early regeneration. Furthermore, endothelial proliferation and a few inflammatory cells were seen in the biopsy, suggesting a recent loss of myocytes (Fig. 5a and b). Cyclosporine (200 mg/day) and mycophenolate mofetil (2 g/day) were added to prednisolone (15 mg/day) to attenuate any inflammatory component. Despite stable peripheral muscle function, no convincing cardiac effect appeared. The combination of heart disease and myositis led to test for AMA in April 2020. AMA were present in unmeasurable high titers (>220 [<4 kIU/L]), supporting a diagnosis of cardiomyopathy related to AMA-associated inflammatory myositis (AMA-IM). In May 2020 rituximab therapy was started but unfortunately no cardiac improvement was achieved. Due to severe chronic renal impairment and ultimately liver failure the patient was not a candidate for heart transplantation. He died in cardiogenic and septic shock in July 2020.
DISCUSSION
AMA-IM is a rare and sparsely described disease entity occurring independently or along with other autoimmune conditions, especially PBC [1–3]. Two previous case series found AMA in 0.006 and 11.3%, respectively, of patients with inflammatory myopathy—a variation probably reflecting the limited amount of data in a rare entity [1, 2]. Cardiac involvement of AMA-IM is a rather new recognition only described by a few, previous case reports/series within the last decades [1–5].
Little is known about the clinical and histopathological phenotype of AMA-IM. In consistency with our observations, previous cases report polymorph cardiac involvement including arrhythmias, cardiomyopathy and heart failure as prominent clinical features [1–6], and muscle biopsies with varying degrees of inflammation, atrophy and fibrosis [1, 3–5].
Our patient developed PAF at age 35, which was perceived as a complication to Graves thyrotoxicosis. Retrospectively, PAF could have been an initial symptom of AMA-IM, as it continued despite normalization of thyroid function, and was succeeded by severe conduction abnormalities, rising total CK and decreasing muscle strength over the following years. Previous reports confirm that cardiac manifestations often precede muscle symptoms in AMA-IM, increasing the risk of misdiagnosing [1, 2]. In our case, the diagnostic process was further challenged by ambiguous test results as MSAs and ANA screening appeared normal, and neither imaging nor biopsies showed active inflammation. The muscle biopsy showed a necrotizing myopathy, which was not associated to statin as Atorvastatin was prescribed years after the onset of muscle involvement and no anti-HMGCR antibodies were detected. In the endomyocardial biopsy, myocarditis was not directly observed. However, the focal loss of myocytes and replacement with alcian positive material as part of the regenerative process suggests a recent damaging event, which may be myocarditis. The CMRI findings of LGE following cardiac arrest could be due to coronary thromboembolism or an inflammatory process of the myocardium. The former seems unlikely given the normal coronary arteries on the previous CAG. Hence, the initially sparse muscle symptoms and prolonged diagnostic process with step-wise exclusion of genetic -, other rheumatic-, ischemic- and malignant diseases, before AMA testing provided a final diagnosis, caused a treatment delay, which might in part explain the insufficient cardiac responsiveness to immune suppressants in our patient. However, a diminished cardiac versus muscular response to immunosuppressants in AMA-IM has been observed in previous cases, across genders, disease durations and drug types [1, 2, 4, 5]. Taken together, this might point to a need for more aggressive strategies to reverse the cardiac manifestations.
In conclusion, our case supports that cardiac involvement can be a severe complication in AMA-IM and emphasizes the importance of testing for AMA in etiologically unclarified inflammatory myopathies and cardiac failure. The lack of treatment effect on cardiac failure in our and previous cases may indicate that very early and aggressive management of heart involvement is necessary. However, future systematic studies are needed to clarify the optimal treatment strategies for this disease entity.
ACKNOWLEDGEMENTS
None.
CONFLICT OF INTEREST STATEMENT
P.H., N.W., K.R., R.P., P.H.A., T.H.LJ. and L.D. declare no conflicts of interest.
FUNDING
There was no funding for this case report.
ETHICAL APPROVAL
No approval from the Ethics Committee is required for this study according to Danish Legislation.
CONSENT
A written consent form has been fulfilled by the patient.
GUARANTOR
Louise Pyndt Diederichsen, MD, PhD. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB | DrugsGivenReaction | CC BY-NC | 33732479 | 20,074,331 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Cardiac arrest in anti-mitochondrial antibody associated inflammatory myopathy.
Insight into predictors of cardiac involvement in inflammatory myopathies is sparse. A negative prognostic role of anti-mitochondrial antibodies (AMA) has been noticed and is supported by the current case. We describe a male patient who at the age 40 suffered a cardiac arrest and over the following months experienced progressive heart failure, arrhythmias and proximal muscle weakness. Clinical, genetic and serologic testing and repeated imaging- and histopathological investigations resulted in a diagnosis of AMA-associated, necrotizing, inflammatory myositis with cardiac involvement. Besides a cardiac resynchronization therapy defibrillator, heart failure and antiarrhythmic drugs the patient received successive immunosuppressants, which improved skeletal muscle strength but not cardiac disease progression. At age 45 he died from end-stage heart failure. Clinicians must be aware of AMA-associated myositis as a cause of unclarified heart disease, even in patients with initially sparse extra-cardiac manifestations. Further knowledge of treatment strategies is highly needed for this disease entity.
INTRODUCTION
Inflammatory myopathy is a heterogeneous disease entity affecting primarily the skeletal muscles. Anti-mitochondrial antibodies (AMA)—the serological hallmark of primary biliary cholangitis (PBC)—exist in a subgroup of myositis patients and may predict serious cardiac involvement [1, 2]. Awareness of AMA and their pathophysiological role in myositis is of great therapeutic and prognostic relevance as illustrated by this case.
Figure 1 Electrocardiogram after resuscitation for cardiac arrest showing atrial fibrillation, ventricular extra systoles and q-waves along the anterior leads.
Figure 2 Cardiac magnetic resonance imaging (CMRI). Late gadolinium enhancement images in the short axis (a), and four chamber (b) of the heart. The arrows point to the pathologic area of the myocardium (white area in the background of normal, black, myocardium).
Figure 3 Serological disease activity markers including levels of Troponin-I (TN-I), pro B-type Natriuretic Peptide (pro-BNP) and total Creatine Kinase (CK) over time and in relation to the clinical course and treatment with Prednisolone (Pred.)/*methylprednisolone, Methotrexate (MTX), Ciclosporin (Cicl.), Mycophenolate mofetil (Mmf) and Rituximab (Rtx).
Figure 4 Cardiac PET-CT with F-18-FDG/Rb-82 revealing nonviable perfusion defect in the apex and the lateral wall of the left ventricle (arrows).
Figure 5 Histopathological images of myocardial biopsy showing (a, HE) mild to moderate hypertrophy and replacement fibrosis (arrow) with endothelial proliferation, few inflammatory cells and (b, AVG) alcian-positivity (arrow).
CASE REPORT
A 40-year-old male with a medical history of Graves’ disease and paroxysmal atrial flutter (PAF) was admitted to the hospital on February 2016 after resuscitation for cardiac arrest/ventricular fibrillation (VF). He had no risk factors for ischemic heart disease. At arrival to the hospital, the electrocardiogram showed atrial fibrillation, ventricular extra systoles and q-waves in anterior leads (Fig. 1). In hospital heart monitoring showed paroxysmal complete heart block. Blood tests revealed elevated troponin-T (262, [<14 ng/L]), creatine kinase (CK) myocardial band (46,1 [<7 μg/L]) and total CK (2530 [25–400 U/l]). Chest X-ray showed cardiomegaly, and transthoracic echocardiography (TTE) disclosed dilatation of left ventricle with ejection fractions (LVEF) of 25–30%, hypofunction of right ventricle and inferoseptal akinesia. Coronary angiography (CAG) showed normal coronary arteries. Cardiac magnetic resonance imaging (CMRI) confirmed inferoseptal akinesia of the distal part of the myocardium in the left ventricle where late gadolinium enhancement (LGE) was found in a subendocardial, almost transmural pattern (Fig. 2a and b). A Cardiac-Resynchronization-Therapy-Defibrillator device (CRT-D) was implanted, and anticoagulants, antiarrhythmics, statin and heart failure therapy were started. The patient complained of muscle weakness for 2 years. Medical records showed elevated total CK (2000–3000 U/l) tracing back to 2014. Muscle strength testing confirmed proximal weakness of all extremities but no other signs of rheumatic/neurologic disease. The patient was subsequently followed by both cardiologists and neurologists, where progressive muscular weakness, repetitive supraventricular and ventricular arrhythmias and elevated cardiac/muscle enzymes were registered between 2016 and 2017 (Fig. 3). Serological tests for myositis-specific autoantibodies (MSAs) including anti-HMGCR, ANA and genetics for neuromuscular diseases were negative. Whole-body positron-emission-tomography computed-tomography (PET-CT) and pulmonary function tests were normal. Muscle biopsy showed fiber variability and cell necrosis compatible with immune-mediated, necrotizing myopathy. Prednisolone (75 mg/day) was initiated in January 2018 resulting in improved physical performance. In March 2018 methotrexate (MTX) (15–25 mg/week) was added and prednisolone tapered, resulting in continued clinical improvement and stable LVEF of 35%. In March 2019, while treated with MTX (20 mg/week) monotherapy, the patient experienced worsening of muscle weakness and dyspnea. Blood tests showed rising total CK (Fig. 3) and X-ray revealed pulmonary congestion. The condition improved transitorily on diuretics and increased MTX (25 mg/week). Six months later, the patient was brought to intensive care in cardiogenic shock due to decompensated severe biventricular failure. He was stabilized by inotropic support, diuretics, amiodarone, upregulation of CRT pace and glucocorticoids. TTE depicted biventricular hypofunction/dilatation (LVEF 10–15%), and a cardiac PET-CT (F-18-FDG/Rb-82) showed nonviable perfusion defect in the apex and lateral wall of the left ventricle (Fig. 4). A myocardial biopsy revealed mild to moderate hypertrophy and maturing replacement fibrosis with alcian-positive matrix indicating the presence of glycosaminoglycans as seen in early regeneration. Furthermore, endothelial proliferation and a few inflammatory cells were seen in the biopsy, suggesting a recent loss of myocytes (Fig. 5a and b). Cyclosporine (200 mg/day) and mycophenolate mofetil (2 g/day) were added to prednisolone (15 mg/day) to attenuate any inflammatory component. Despite stable peripheral muscle function, no convincing cardiac effect appeared. The combination of heart disease and myositis led to test for AMA in April 2020. AMA were present in unmeasurable high titers (>220 [<4 kIU/L]), supporting a diagnosis of cardiomyopathy related to AMA-associated inflammatory myositis (AMA-IM). In May 2020 rituximab therapy was started but unfortunately no cardiac improvement was achieved. Due to severe chronic renal impairment and ultimately liver failure the patient was not a candidate for heart transplantation. He died in cardiogenic and septic shock in July 2020.
DISCUSSION
AMA-IM is a rare and sparsely described disease entity occurring independently or along with other autoimmune conditions, especially PBC [1–3]. Two previous case series found AMA in 0.006 and 11.3%, respectively, of patients with inflammatory myopathy—a variation probably reflecting the limited amount of data in a rare entity [1, 2]. Cardiac involvement of AMA-IM is a rather new recognition only described by a few, previous case reports/series within the last decades [1–5].
Little is known about the clinical and histopathological phenotype of AMA-IM. In consistency with our observations, previous cases report polymorph cardiac involvement including arrhythmias, cardiomyopathy and heart failure as prominent clinical features [1–6], and muscle biopsies with varying degrees of inflammation, atrophy and fibrosis [1, 3–5].
Our patient developed PAF at age 35, which was perceived as a complication to Graves thyrotoxicosis. Retrospectively, PAF could have been an initial symptom of AMA-IM, as it continued despite normalization of thyroid function, and was succeeded by severe conduction abnormalities, rising total CK and decreasing muscle strength over the following years. Previous reports confirm that cardiac manifestations often precede muscle symptoms in AMA-IM, increasing the risk of misdiagnosing [1, 2]. In our case, the diagnostic process was further challenged by ambiguous test results as MSAs and ANA screening appeared normal, and neither imaging nor biopsies showed active inflammation. The muscle biopsy showed a necrotizing myopathy, which was not associated to statin as Atorvastatin was prescribed years after the onset of muscle involvement and no anti-HMGCR antibodies were detected. In the endomyocardial biopsy, myocarditis was not directly observed. However, the focal loss of myocytes and replacement with alcian positive material as part of the regenerative process suggests a recent damaging event, which may be myocarditis. The CMRI findings of LGE following cardiac arrest could be due to coronary thromboembolism or an inflammatory process of the myocardium. The former seems unlikely given the normal coronary arteries on the previous CAG. Hence, the initially sparse muscle symptoms and prolonged diagnostic process with step-wise exclusion of genetic -, other rheumatic-, ischemic- and malignant diseases, before AMA testing provided a final diagnosis, caused a treatment delay, which might in part explain the insufficient cardiac responsiveness to immune suppressants in our patient. However, a diminished cardiac versus muscular response to immunosuppressants in AMA-IM has been observed in previous cases, across genders, disease durations and drug types [1, 2, 4, 5]. Taken together, this might point to a need for more aggressive strategies to reverse the cardiac manifestations.
In conclusion, our case supports that cardiac involvement can be a severe complication in AMA-IM and emphasizes the importance of testing for AMA in etiologically unclarified inflammatory myopathies and cardiac failure. The lack of treatment effect on cardiac failure in our and previous cases may indicate that very early and aggressive management of heart involvement is necessary. However, future systematic studies are needed to clarify the optimal treatment strategies for this disease entity.
ACKNOWLEDGEMENTS
None.
CONFLICT OF INTEREST STATEMENT
P.H., N.W., K.R., R.P., P.H.A., T.H.LJ. and L.D. declare no conflicts of interest.
FUNDING
There was no funding for this case report.
ETHICAL APPROVAL
No approval from the Ethics Committee is required for this study according to Danish Legislation.
CONSENT
A written consent form has been fulfilled by the patient.
GUARANTOR
Louise Pyndt Diederichsen, MD, PhD. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB | DrugsGivenReaction | CC BY-NC | 33732479 | 20,074,331 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Septic shock'. | Cardiac arrest in anti-mitochondrial antibody associated inflammatory myopathy.
Insight into predictors of cardiac involvement in inflammatory myopathies is sparse. A negative prognostic role of anti-mitochondrial antibodies (AMA) has been noticed and is supported by the current case. We describe a male patient who at the age 40 suffered a cardiac arrest and over the following months experienced progressive heart failure, arrhythmias and proximal muscle weakness. Clinical, genetic and serologic testing and repeated imaging- and histopathological investigations resulted in a diagnosis of AMA-associated, necrotizing, inflammatory myositis with cardiac involvement. Besides a cardiac resynchronization therapy defibrillator, heart failure and antiarrhythmic drugs the patient received successive immunosuppressants, which improved skeletal muscle strength but not cardiac disease progression. At age 45 he died from end-stage heart failure. Clinicians must be aware of AMA-associated myositis as a cause of unclarified heart disease, even in patients with initially sparse extra-cardiac manifestations. Further knowledge of treatment strategies is highly needed for this disease entity.
INTRODUCTION
Inflammatory myopathy is a heterogeneous disease entity affecting primarily the skeletal muscles. Anti-mitochondrial antibodies (AMA)—the serological hallmark of primary biliary cholangitis (PBC)—exist in a subgroup of myositis patients and may predict serious cardiac involvement [1, 2]. Awareness of AMA and their pathophysiological role in myositis is of great therapeutic and prognostic relevance as illustrated by this case.
Figure 1 Electrocardiogram after resuscitation for cardiac arrest showing atrial fibrillation, ventricular extra systoles and q-waves along the anterior leads.
Figure 2 Cardiac magnetic resonance imaging (CMRI). Late gadolinium enhancement images in the short axis (a), and four chamber (b) of the heart. The arrows point to the pathologic area of the myocardium (white area in the background of normal, black, myocardium).
Figure 3 Serological disease activity markers including levels of Troponin-I (TN-I), pro B-type Natriuretic Peptide (pro-BNP) and total Creatine Kinase (CK) over time and in relation to the clinical course and treatment with Prednisolone (Pred.)/*methylprednisolone, Methotrexate (MTX), Ciclosporin (Cicl.), Mycophenolate mofetil (Mmf) and Rituximab (Rtx).
Figure 4 Cardiac PET-CT with F-18-FDG/Rb-82 revealing nonviable perfusion defect in the apex and the lateral wall of the left ventricle (arrows).
Figure 5 Histopathological images of myocardial biopsy showing (a, HE) mild to moderate hypertrophy and replacement fibrosis (arrow) with endothelial proliferation, few inflammatory cells and (b, AVG) alcian-positivity (arrow).
CASE REPORT
A 40-year-old male with a medical history of Graves’ disease and paroxysmal atrial flutter (PAF) was admitted to the hospital on February 2016 after resuscitation for cardiac arrest/ventricular fibrillation (VF). He had no risk factors for ischemic heart disease. At arrival to the hospital, the electrocardiogram showed atrial fibrillation, ventricular extra systoles and q-waves in anterior leads (Fig. 1). In hospital heart monitoring showed paroxysmal complete heart block. Blood tests revealed elevated troponin-T (262, [<14 ng/L]), creatine kinase (CK) myocardial band (46,1 [<7 μg/L]) and total CK (2530 [25–400 U/l]). Chest X-ray showed cardiomegaly, and transthoracic echocardiography (TTE) disclosed dilatation of left ventricle with ejection fractions (LVEF) of 25–30%, hypofunction of right ventricle and inferoseptal akinesia. Coronary angiography (CAG) showed normal coronary arteries. Cardiac magnetic resonance imaging (CMRI) confirmed inferoseptal akinesia of the distal part of the myocardium in the left ventricle where late gadolinium enhancement (LGE) was found in a subendocardial, almost transmural pattern (Fig. 2a and b). A Cardiac-Resynchronization-Therapy-Defibrillator device (CRT-D) was implanted, and anticoagulants, antiarrhythmics, statin and heart failure therapy were started. The patient complained of muscle weakness for 2 years. Medical records showed elevated total CK (2000–3000 U/l) tracing back to 2014. Muscle strength testing confirmed proximal weakness of all extremities but no other signs of rheumatic/neurologic disease. The patient was subsequently followed by both cardiologists and neurologists, where progressive muscular weakness, repetitive supraventricular and ventricular arrhythmias and elevated cardiac/muscle enzymes were registered between 2016 and 2017 (Fig. 3). Serological tests for myositis-specific autoantibodies (MSAs) including anti-HMGCR, ANA and genetics for neuromuscular diseases were negative. Whole-body positron-emission-tomography computed-tomography (PET-CT) and pulmonary function tests were normal. Muscle biopsy showed fiber variability and cell necrosis compatible with immune-mediated, necrotizing myopathy. Prednisolone (75 mg/day) was initiated in January 2018 resulting in improved physical performance. In March 2018 methotrexate (MTX) (15–25 mg/week) was added and prednisolone tapered, resulting in continued clinical improvement and stable LVEF of 35%. In March 2019, while treated with MTX (20 mg/week) monotherapy, the patient experienced worsening of muscle weakness and dyspnea. Blood tests showed rising total CK (Fig. 3) and X-ray revealed pulmonary congestion. The condition improved transitorily on diuretics and increased MTX (25 mg/week). Six months later, the patient was brought to intensive care in cardiogenic shock due to decompensated severe biventricular failure. He was stabilized by inotropic support, diuretics, amiodarone, upregulation of CRT pace and glucocorticoids. TTE depicted biventricular hypofunction/dilatation (LVEF 10–15%), and a cardiac PET-CT (F-18-FDG/Rb-82) showed nonviable perfusion defect in the apex and lateral wall of the left ventricle (Fig. 4). A myocardial biopsy revealed mild to moderate hypertrophy and maturing replacement fibrosis with alcian-positive matrix indicating the presence of glycosaminoglycans as seen in early regeneration. Furthermore, endothelial proliferation and a few inflammatory cells were seen in the biopsy, suggesting a recent loss of myocytes (Fig. 5a and b). Cyclosporine (200 mg/day) and mycophenolate mofetil (2 g/day) were added to prednisolone (15 mg/day) to attenuate any inflammatory component. Despite stable peripheral muscle function, no convincing cardiac effect appeared. The combination of heart disease and myositis led to test for AMA in April 2020. AMA were present in unmeasurable high titers (>220 [<4 kIU/L]), supporting a diagnosis of cardiomyopathy related to AMA-associated inflammatory myositis (AMA-IM). In May 2020 rituximab therapy was started but unfortunately no cardiac improvement was achieved. Due to severe chronic renal impairment and ultimately liver failure the patient was not a candidate for heart transplantation. He died in cardiogenic and septic shock in July 2020.
DISCUSSION
AMA-IM is a rare and sparsely described disease entity occurring independently or along with other autoimmune conditions, especially PBC [1–3]. Two previous case series found AMA in 0.006 and 11.3%, respectively, of patients with inflammatory myopathy—a variation probably reflecting the limited amount of data in a rare entity [1, 2]. Cardiac involvement of AMA-IM is a rather new recognition only described by a few, previous case reports/series within the last decades [1–5].
Little is known about the clinical and histopathological phenotype of AMA-IM. In consistency with our observations, previous cases report polymorph cardiac involvement including arrhythmias, cardiomyopathy and heart failure as prominent clinical features [1–6], and muscle biopsies with varying degrees of inflammation, atrophy and fibrosis [1, 3–5].
Our patient developed PAF at age 35, which was perceived as a complication to Graves thyrotoxicosis. Retrospectively, PAF could have been an initial symptom of AMA-IM, as it continued despite normalization of thyroid function, and was succeeded by severe conduction abnormalities, rising total CK and decreasing muscle strength over the following years. Previous reports confirm that cardiac manifestations often precede muscle symptoms in AMA-IM, increasing the risk of misdiagnosing [1, 2]. In our case, the diagnostic process was further challenged by ambiguous test results as MSAs and ANA screening appeared normal, and neither imaging nor biopsies showed active inflammation. The muscle biopsy showed a necrotizing myopathy, which was not associated to statin as Atorvastatin was prescribed years after the onset of muscle involvement and no anti-HMGCR antibodies were detected. In the endomyocardial biopsy, myocarditis was not directly observed. However, the focal loss of myocytes and replacement with alcian positive material as part of the regenerative process suggests a recent damaging event, which may be myocarditis. The CMRI findings of LGE following cardiac arrest could be due to coronary thromboembolism or an inflammatory process of the myocardium. The former seems unlikely given the normal coronary arteries on the previous CAG. Hence, the initially sparse muscle symptoms and prolonged diagnostic process with step-wise exclusion of genetic -, other rheumatic-, ischemic- and malignant diseases, before AMA testing provided a final diagnosis, caused a treatment delay, which might in part explain the insufficient cardiac responsiveness to immune suppressants in our patient. However, a diminished cardiac versus muscular response to immunosuppressants in AMA-IM has been observed in previous cases, across genders, disease durations and drug types [1, 2, 4, 5]. Taken together, this might point to a need for more aggressive strategies to reverse the cardiac manifestations.
In conclusion, our case supports that cardiac involvement can be a severe complication in AMA-IM and emphasizes the importance of testing for AMA in etiologically unclarified inflammatory myopathies and cardiac failure. The lack of treatment effect on cardiac failure in our and previous cases may indicate that very early and aggressive management of heart involvement is necessary. However, future systematic studies are needed to clarify the optimal treatment strategies for this disease entity.
ACKNOWLEDGEMENTS
None.
CONFLICT OF INTEREST STATEMENT
P.H., N.W., K.R., R.P., P.H.A., T.H.LJ. and L.D. declare no conflicts of interest.
FUNDING
There was no funding for this case report.
ETHICAL APPROVAL
No approval from the Ethics Committee is required for this study according to Danish Legislation.
CONSENT
A written consent form has been fulfilled by the patient.
GUARANTOR
Louise Pyndt Diederichsen, MD, PhD. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB | DrugsGivenReaction | CC BY-NC | 33732479 | 20,074,331 | 2021-03 |
What was the outcome of reaction 'Cardiogenic shock'? | Cardiac arrest in anti-mitochondrial antibody associated inflammatory myopathy.
Insight into predictors of cardiac involvement in inflammatory myopathies is sparse. A negative prognostic role of anti-mitochondrial antibodies (AMA) has been noticed and is supported by the current case. We describe a male patient who at the age 40 suffered a cardiac arrest and over the following months experienced progressive heart failure, arrhythmias and proximal muscle weakness. Clinical, genetic and serologic testing and repeated imaging- and histopathological investigations resulted in a diagnosis of AMA-associated, necrotizing, inflammatory myositis with cardiac involvement. Besides a cardiac resynchronization therapy defibrillator, heart failure and antiarrhythmic drugs the patient received successive immunosuppressants, which improved skeletal muscle strength but not cardiac disease progression. At age 45 he died from end-stage heart failure. Clinicians must be aware of AMA-associated myositis as a cause of unclarified heart disease, even in patients with initially sparse extra-cardiac manifestations. Further knowledge of treatment strategies is highly needed for this disease entity.
INTRODUCTION
Inflammatory myopathy is a heterogeneous disease entity affecting primarily the skeletal muscles. Anti-mitochondrial antibodies (AMA)—the serological hallmark of primary biliary cholangitis (PBC)—exist in a subgroup of myositis patients and may predict serious cardiac involvement [1, 2]. Awareness of AMA and their pathophysiological role in myositis is of great therapeutic and prognostic relevance as illustrated by this case.
Figure 1 Electrocardiogram after resuscitation for cardiac arrest showing atrial fibrillation, ventricular extra systoles and q-waves along the anterior leads.
Figure 2 Cardiac magnetic resonance imaging (CMRI). Late gadolinium enhancement images in the short axis (a), and four chamber (b) of the heart. The arrows point to the pathologic area of the myocardium (white area in the background of normal, black, myocardium).
Figure 3 Serological disease activity markers including levels of Troponin-I (TN-I), pro B-type Natriuretic Peptide (pro-BNP) and total Creatine Kinase (CK) over time and in relation to the clinical course and treatment with Prednisolone (Pred.)/*methylprednisolone, Methotrexate (MTX), Ciclosporin (Cicl.), Mycophenolate mofetil (Mmf) and Rituximab (Rtx).
Figure 4 Cardiac PET-CT with F-18-FDG/Rb-82 revealing nonviable perfusion defect in the apex and the lateral wall of the left ventricle (arrows).
Figure 5 Histopathological images of myocardial biopsy showing (a, HE) mild to moderate hypertrophy and replacement fibrosis (arrow) with endothelial proliferation, few inflammatory cells and (b, AVG) alcian-positivity (arrow).
CASE REPORT
A 40-year-old male with a medical history of Graves’ disease and paroxysmal atrial flutter (PAF) was admitted to the hospital on February 2016 after resuscitation for cardiac arrest/ventricular fibrillation (VF). He had no risk factors for ischemic heart disease. At arrival to the hospital, the electrocardiogram showed atrial fibrillation, ventricular extra systoles and q-waves in anterior leads (Fig. 1). In hospital heart monitoring showed paroxysmal complete heart block. Blood tests revealed elevated troponin-T (262, [<14 ng/L]), creatine kinase (CK) myocardial band (46,1 [<7 μg/L]) and total CK (2530 [25–400 U/l]). Chest X-ray showed cardiomegaly, and transthoracic echocardiography (TTE) disclosed dilatation of left ventricle with ejection fractions (LVEF) of 25–30%, hypofunction of right ventricle and inferoseptal akinesia. Coronary angiography (CAG) showed normal coronary arteries. Cardiac magnetic resonance imaging (CMRI) confirmed inferoseptal akinesia of the distal part of the myocardium in the left ventricle where late gadolinium enhancement (LGE) was found in a subendocardial, almost transmural pattern (Fig. 2a and b). A Cardiac-Resynchronization-Therapy-Defibrillator device (CRT-D) was implanted, and anticoagulants, antiarrhythmics, statin and heart failure therapy were started. The patient complained of muscle weakness for 2 years. Medical records showed elevated total CK (2000–3000 U/l) tracing back to 2014. Muscle strength testing confirmed proximal weakness of all extremities but no other signs of rheumatic/neurologic disease. The patient was subsequently followed by both cardiologists and neurologists, where progressive muscular weakness, repetitive supraventricular and ventricular arrhythmias and elevated cardiac/muscle enzymes were registered between 2016 and 2017 (Fig. 3). Serological tests for myositis-specific autoantibodies (MSAs) including anti-HMGCR, ANA and genetics for neuromuscular diseases were negative. Whole-body positron-emission-tomography computed-tomography (PET-CT) and pulmonary function tests were normal. Muscle biopsy showed fiber variability and cell necrosis compatible with immune-mediated, necrotizing myopathy. Prednisolone (75 mg/day) was initiated in January 2018 resulting in improved physical performance. In March 2018 methotrexate (MTX) (15–25 mg/week) was added and prednisolone tapered, resulting in continued clinical improvement and stable LVEF of 35%. In March 2019, while treated with MTX (20 mg/week) monotherapy, the patient experienced worsening of muscle weakness and dyspnea. Blood tests showed rising total CK (Fig. 3) and X-ray revealed pulmonary congestion. The condition improved transitorily on diuretics and increased MTX (25 mg/week). Six months later, the patient was brought to intensive care in cardiogenic shock due to decompensated severe biventricular failure. He was stabilized by inotropic support, diuretics, amiodarone, upregulation of CRT pace and glucocorticoids. TTE depicted biventricular hypofunction/dilatation (LVEF 10–15%), and a cardiac PET-CT (F-18-FDG/Rb-82) showed nonviable perfusion defect in the apex and lateral wall of the left ventricle (Fig. 4). A myocardial biopsy revealed mild to moderate hypertrophy and maturing replacement fibrosis with alcian-positive matrix indicating the presence of glycosaminoglycans as seen in early regeneration. Furthermore, endothelial proliferation and a few inflammatory cells were seen in the biopsy, suggesting a recent loss of myocytes (Fig. 5a and b). Cyclosporine (200 mg/day) and mycophenolate mofetil (2 g/day) were added to prednisolone (15 mg/day) to attenuate any inflammatory component. Despite stable peripheral muscle function, no convincing cardiac effect appeared. The combination of heart disease and myositis led to test for AMA in April 2020. AMA were present in unmeasurable high titers (>220 [<4 kIU/L]), supporting a diagnosis of cardiomyopathy related to AMA-associated inflammatory myositis (AMA-IM). In May 2020 rituximab therapy was started but unfortunately no cardiac improvement was achieved. Due to severe chronic renal impairment and ultimately liver failure the patient was not a candidate for heart transplantation. He died in cardiogenic and septic shock in July 2020.
DISCUSSION
AMA-IM is a rare and sparsely described disease entity occurring independently or along with other autoimmune conditions, especially PBC [1–3]. Two previous case series found AMA in 0.006 and 11.3%, respectively, of patients with inflammatory myopathy—a variation probably reflecting the limited amount of data in a rare entity [1, 2]. Cardiac involvement of AMA-IM is a rather new recognition only described by a few, previous case reports/series within the last decades [1–5].
Little is known about the clinical and histopathological phenotype of AMA-IM. In consistency with our observations, previous cases report polymorph cardiac involvement including arrhythmias, cardiomyopathy and heart failure as prominent clinical features [1–6], and muscle biopsies with varying degrees of inflammation, atrophy and fibrosis [1, 3–5].
Our patient developed PAF at age 35, which was perceived as a complication to Graves thyrotoxicosis. Retrospectively, PAF could have been an initial symptom of AMA-IM, as it continued despite normalization of thyroid function, and was succeeded by severe conduction abnormalities, rising total CK and decreasing muscle strength over the following years. Previous reports confirm that cardiac manifestations often precede muscle symptoms in AMA-IM, increasing the risk of misdiagnosing [1, 2]. In our case, the diagnostic process was further challenged by ambiguous test results as MSAs and ANA screening appeared normal, and neither imaging nor biopsies showed active inflammation. The muscle biopsy showed a necrotizing myopathy, which was not associated to statin as Atorvastatin was prescribed years after the onset of muscle involvement and no anti-HMGCR antibodies were detected. In the endomyocardial biopsy, myocarditis was not directly observed. However, the focal loss of myocytes and replacement with alcian positive material as part of the regenerative process suggests a recent damaging event, which may be myocarditis. The CMRI findings of LGE following cardiac arrest could be due to coronary thromboembolism or an inflammatory process of the myocardium. The former seems unlikely given the normal coronary arteries on the previous CAG. Hence, the initially sparse muscle symptoms and prolonged diagnostic process with step-wise exclusion of genetic -, other rheumatic-, ischemic- and malignant diseases, before AMA testing provided a final diagnosis, caused a treatment delay, which might in part explain the insufficient cardiac responsiveness to immune suppressants in our patient. However, a diminished cardiac versus muscular response to immunosuppressants in AMA-IM has been observed in previous cases, across genders, disease durations and drug types [1, 2, 4, 5]. Taken together, this might point to a need for more aggressive strategies to reverse the cardiac manifestations.
In conclusion, our case supports that cardiac involvement can be a severe complication in AMA-IM and emphasizes the importance of testing for AMA in etiologically unclarified inflammatory myopathies and cardiac failure. The lack of treatment effect on cardiac failure in our and previous cases may indicate that very early and aggressive management of heart involvement is necessary. However, future systematic studies are needed to clarify the optimal treatment strategies for this disease entity.
ACKNOWLEDGEMENTS
None.
CONFLICT OF INTEREST STATEMENT
P.H., N.W., K.R., R.P., P.H.A., T.H.LJ. and L.D. declare no conflicts of interest.
FUNDING
There was no funding for this case report.
ETHICAL APPROVAL
No approval from the Ethics Committee is required for this study according to Danish Legislation.
CONSENT
A written consent form has been fulfilled by the patient.
GUARANTOR
Louise Pyndt Diederichsen, MD, PhD. | Fatal | ReactionOutcome | CC BY-NC | 33732479 | 20,074,331 | 2021-03 |
What was the outcome of reaction 'Off label use'? | Cardiac arrest in anti-mitochondrial antibody associated inflammatory myopathy.
Insight into predictors of cardiac involvement in inflammatory myopathies is sparse. A negative prognostic role of anti-mitochondrial antibodies (AMA) has been noticed and is supported by the current case. We describe a male patient who at the age 40 suffered a cardiac arrest and over the following months experienced progressive heart failure, arrhythmias and proximal muscle weakness. Clinical, genetic and serologic testing and repeated imaging- and histopathological investigations resulted in a diagnosis of AMA-associated, necrotizing, inflammatory myositis with cardiac involvement. Besides a cardiac resynchronization therapy defibrillator, heart failure and antiarrhythmic drugs the patient received successive immunosuppressants, which improved skeletal muscle strength but not cardiac disease progression. At age 45 he died from end-stage heart failure. Clinicians must be aware of AMA-associated myositis as a cause of unclarified heart disease, even in patients with initially sparse extra-cardiac manifestations. Further knowledge of treatment strategies is highly needed for this disease entity.
INTRODUCTION
Inflammatory myopathy is a heterogeneous disease entity affecting primarily the skeletal muscles. Anti-mitochondrial antibodies (AMA)—the serological hallmark of primary biliary cholangitis (PBC)—exist in a subgroup of myositis patients and may predict serious cardiac involvement [1, 2]. Awareness of AMA and their pathophysiological role in myositis is of great therapeutic and prognostic relevance as illustrated by this case.
Figure 1 Electrocardiogram after resuscitation for cardiac arrest showing atrial fibrillation, ventricular extra systoles and q-waves along the anterior leads.
Figure 2 Cardiac magnetic resonance imaging (CMRI). Late gadolinium enhancement images in the short axis (a), and four chamber (b) of the heart. The arrows point to the pathologic area of the myocardium (white area in the background of normal, black, myocardium).
Figure 3 Serological disease activity markers including levels of Troponin-I (TN-I), pro B-type Natriuretic Peptide (pro-BNP) and total Creatine Kinase (CK) over time and in relation to the clinical course and treatment with Prednisolone (Pred.)/*methylprednisolone, Methotrexate (MTX), Ciclosporin (Cicl.), Mycophenolate mofetil (Mmf) and Rituximab (Rtx).
Figure 4 Cardiac PET-CT with F-18-FDG/Rb-82 revealing nonviable perfusion defect in the apex and the lateral wall of the left ventricle (arrows).
Figure 5 Histopathological images of myocardial biopsy showing (a, HE) mild to moderate hypertrophy and replacement fibrosis (arrow) with endothelial proliferation, few inflammatory cells and (b, AVG) alcian-positivity (arrow).
CASE REPORT
A 40-year-old male with a medical history of Graves’ disease and paroxysmal atrial flutter (PAF) was admitted to the hospital on February 2016 after resuscitation for cardiac arrest/ventricular fibrillation (VF). He had no risk factors for ischemic heart disease. At arrival to the hospital, the electrocardiogram showed atrial fibrillation, ventricular extra systoles and q-waves in anterior leads (Fig. 1). In hospital heart monitoring showed paroxysmal complete heart block. Blood tests revealed elevated troponin-T (262, [<14 ng/L]), creatine kinase (CK) myocardial band (46,1 [<7 μg/L]) and total CK (2530 [25–400 U/l]). Chest X-ray showed cardiomegaly, and transthoracic echocardiography (TTE) disclosed dilatation of left ventricle with ejection fractions (LVEF) of 25–30%, hypofunction of right ventricle and inferoseptal akinesia. Coronary angiography (CAG) showed normal coronary arteries. Cardiac magnetic resonance imaging (CMRI) confirmed inferoseptal akinesia of the distal part of the myocardium in the left ventricle where late gadolinium enhancement (LGE) was found in a subendocardial, almost transmural pattern (Fig. 2a and b). A Cardiac-Resynchronization-Therapy-Defibrillator device (CRT-D) was implanted, and anticoagulants, antiarrhythmics, statin and heart failure therapy were started. The patient complained of muscle weakness for 2 years. Medical records showed elevated total CK (2000–3000 U/l) tracing back to 2014. Muscle strength testing confirmed proximal weakness of all extremities but no other signs of rheumatic/neurologic disease. The patient was subsequently followed by both cardiologists and neurologists, where progressive muscular weakness, repetitive supraventricular and ventricular arrhythmias and elevated cardiac/muscle enzymes were registered between 2016 and 2017 (Fig. 3). Serological tests for myositis-specific autoantibodies (MSAs) including anti-HMGCR, ANA and genetics for neuromuscular diseases were negative. Whole-body positron-emission-tomography computed-tomography (PET-CT) and pulmonary function tests were normal. Muscle biopsy showed fiber variability and cell necrosis compatible with immune-mediated, necrotizing myopathy. Prednisolone (75 mg/day) was initiated in January 2018 resulting in improved physical performance. In March 2018 methotrexate (MTX) (15–25 mg/week) was added and prednisolone tapered, resulting in continued clinical improvement and stable LVEF of 35%. In March 2019, while treated with MTX (20 mg/week) monotherapy, the patient experienced worsening of muscle weakness and dyspnea. Blood tests showed rising total CK (Fig. 3) and X-ray revealed pulmonary congestion. The condition improved transitorily on diuretics and increased MTX (25 mg/week). Six months later, the patient was brought to intensive care in cardiogenic shock due to decompensated severe biventricular failure. He was stabilized by inotropic support, diuretics, amiodarone, upregulation of CRT pace and glucocorticoids. TTE depicted biventricular hypofunction/dilatation (LVEF 10–15%), and a cardiac PET-CT (F-18-FDG/Rb-82) showed nonviable perfusion defect in the apex and lateral wall of the left ventricle (Fig. 4). A myocardial biopsy revealed mild to moderate hypertrophy and maturing replacement fibrosis with alcian-positive matrix indicating the presence of glycosaminoglycans as seen in early regeneration. Furthermore, endothelial proliferation and a few inflammatory cells were seen in the biopsy, suggesting a recent loss of myocytes (Fig. 5a and b). Cyclosporine (200 mg/day) and mycophenolate mofetil (2 g/day) were added to prednisolone (15 mg/day) to attenuate any inflammatory component. Despite stable peripheral muscle function, no convincing cardiac effect appeared. The combination of heart disease and myositis led to test for AMA in April 2020. AMA were present in unmeasurable high titers (>220 [<4 kIU/L]), supporting a diagnosis of cardiomyopathy related to AMA-associated inflammatory myositis (AMA-IM). In May 2020 rituximab therapy was started but unfortunately no cardiac improvement was achieved. Due to severe chronic renal impairment and ultimately liver failure the patient was not a candidate for heart transplantation. He died in cardiogenic and septic shock in July 2020.
DISCUSSION
AMA-IM is a rare and sparsely described disease entity occurring independently or along with other autoimmune conditions, especially PBC [1–3]. Two previous case series found AMA in 0.006 and 11.3%, respectively, of patients with inflammatory myopathy—a variation probably reflecting the limited amount of data in a rare entity [1, 2]. Cardiac involvement of AMA-IM is a rather new recognition only described by a few, previous case reports/series within the last decades [1–5].
Little is known about the clinical and histopathological phenotype of AMA-IM. In consistency with our observations, previous cases report polymorph cardiac involvement including arrhythmias, cardiomyopathy and heart failure as prominent clinical features [1–6], and muscle biopsies with varying degrees of inflammation, atrophy and fibrosis [1, 3–5].
Our patient developed PAF at age 35, which was perceived as a complication to Graves thyrotoxicosis. Retrospectively, PAF could have been an initial symptom of AMA-IM, as it continued despite normalization of thyroid function, and was succeeded by severe conduction abnormalities, rising total CK and decreasing muscle strength over the following years. Previous reports confirm that cardiac manifestations often precede muscle symptoms in AMA-IM, increasing the risk of misdiagnosing [1, 2]. In our case, the diagnostic process was further challenged by ambiguous test results as MSAs and ANA screening appeared normal, and neither imaging nor biopsies showed active inflammation. The muscle biopsy showed a necrotizing myopathy, which was not associated to statin as Atorvastatin was prescribed years after the onset of muscle involvement and no anti-HMGCR antibodies were detected. In the endomyocardial biopsy, myocarditis was not directly observed. However, the focal loss of myocytes and replacement with alcian positive material as part of the regenerative process suggests a recent damaging event, which may be myocarditis. The CMRI findings of LGE following cardiac arrest could be due to coronary thromboembolism or an inflammatory process of the myocardium. The former seems unlikely given the normal coronary arteries on the previous CAG. Hence, the initially sparse muscle symptoms and prolonged diagnostic process with step-wise exclusion of genetic -, other rheumatic-, ischemic- and malignant diseases, before AMA testing provided a final diagnosis, caused a treatment delay, which might in part explain the insufficient cardiac responsiveness to immune suppressants in our patient. However, a diminished cardiac versus muscular response to immunosuppressants in AMA-IM has been observed in previous cases, across genders, disease durations and drug types [1, 2, 4, 5]. Taken together, this might point to a need for more aggressive strategies to reverse the cardiac manifestations.
In conclusion, our case supports that cardiac involvement can be a severe complication in AMA-IM and emphasizes the importance of testing for AMA in etiologically unclarified inflammatory myopathies and cardiac failure. The lack of treatment effect on cardiac failure in our and previous cases may indicate that very early and aggressive management of heart involvement is necessary. However, future systematic studies are needed to clarify the optimal treatment strategies for this disease entity.
ACKNOWLEDGEMENTS
None.
CONFLICT OF INTEREST STATEMENT
P.H., N.W., K.R., R.P., P.H.A., T.H.LJ. and L.D. declare no conflicts of interest.
FUNDING
There was no funding for this case report.
ETHICAL APPROVAL
No approval from the Ethics Committee is required for this study according to Danish Legislation.
CONSENT
A written consent form has been fulfilled by the patient.
GUARANTOR
Louise Pyndt Diederichsen, MD, PhD. | Fatal | ReactionOutcome | CC BY-NC | 33732479 | 20,074,331 | 2021-03 |
What was the outcome of reaction 'Septic shock'? | Cardiac arrest in anti-mitochondrial antibody associated inflammatory myopathy.
Insight into predictors of cardiac involvement in inflammatory myopathies is sparse. A negative prognostic role of anti-mitochondrial antibodies (AMA) has been noticed and is supported by the current case. We describe a male patient who at the age 40 suffered a cardiac arrest and over the following months experienced progressive heart failure, arrhythmias and proximal muscle weakness. Clinical, genetic and serologic testing and repeated imaging- and histopathological investigations resulted in a diagnosis of AMA-associated, necrotizing, inflammatory myositis with cardiac involvement. Besides a cardiac resynchronization therapy defibrillator, heart failure and antiarrhythmic drugs the patient received successive immunosuppressants, which improved skeletal muscle strength but not cardiac disease progression. At age 45 he died from end-stage heart failure. Clinicians must be aware of AMA-associated myositis as a cause of unclarified heart disease, even in patients with initially sparse extra-cardiac manifestations. Further knowledge of treatment strategies is highly needed for this disease entity.
INTRODUCTION
Inflammatory myopathy is a heterogeneous disease entity affecting primarily the skeletal muscles. Anti-mitochondrial antibodies (AMA)—the serological hallmark of primary biliary cholangitis (PBC)—exist in a subgroup of myositis patients and may predict serious cardiac involvement [1, 2]. Awareness of AMA and their pathophysiological role in myositis is of great therapeutic and prognostic relevance as illustrated by this case.
Figure 1 Electrocardiogram after resuscitation for cardiac arrest showing atrial fibrillation, ventricular extra systoles and q-waves along the anterior leads.
Figure 2 Cardiac magnetic resonance imaging (CMRI). Late gadolinium enhancement images in the short axis (a), and four chamber (b) of the heart. The arrows point to the pathologic area of the myocardium (white area in the background of normal, black, myocardium).
Figure 3 Serological disease activity markers including levels of Troponin-I (TN-I), pro B-type Natriuretic Peptide (pro-BNP) and total Creatine Kinase (CK) over time and in relation to the clinical course and treatment with Prednisolone (Pred.)/*methylprednisolone, Methotrexate (MTX), Ciclosporin (Cicl.), Mycophenolate mofetil (Mmf) and Rituximab (Rtx).
Figure 4 Cardiac PET-CT with F-18-FDG/Rb-82 revealing nonviable perfusion defect in the apex and the lateral wall of the left ventricle (arrows).
Figure 5 Histopathological images of myocardial biopsy showing (a, HE) mild to moderate hypertrophy and replacement fibrosis (arrow) with endothelial proliferation, few inflammatory cells and (b, AVG) alcian-positivity (arrow).
CASE REPORT
A 40-year-old male with a medical history of Graves’ disease and paroxysmal atrial flutter (PAF) was admitted to the hospital on February 2016 after resuscitation for cardiac arrest/ventricular fibrillation (VF). He had no risk factors for ischemic heart disease. At arrival to the hospital, the electrocardiogram showed atrial fibrillation, ventricular extra systoles and q-waves in anterior leads (Fig. 1). In hospital heart monitoring showed paroxysmal complete heart block. Blood tests revealed elevated troponin-T (262, [<14 ng/L]), creatine kinase (CK) myocardial band (46,1 [<7 μg/L]) and total CK (2530 [25–400 U/l]). Chest X-ray showed cardiomegaly, and transthoracic echocardiography (TTE) disclosed dilatation of left ventricle with ejection fractions (LVEF) of 25–30%, hypofunction of right ventricle and inferoseptal akinesia. Coronary angiography (CAG) showed normal coronary arteries. Cardiac magnetic resonance imaging (CMRI) confirmed inferoseptal akinesia of the distal part of the myocardium in the left ventricle where late gadolinium enhancement (LGE) was found in a subendocardial, almost transmural pattern (Fig. 2a and b). A Cardiac-Resynchronization-Therapy-Defibrillator device (CRT-D) was implanted, and anticoagulants, antiarrhythmics, statin and heart failure therapy were started. The patient complained of muscle weakness for 2 years. Medical records showed elevated total CK (2000–3000 U/l) tracing back to 2014. Muscle strength testing confirmed proximal weakness of all extremities but no other signs of rheumatic/neurologic disease. The patient was subsequently followed by both cardiologists and neurologists, where progressive muscular weakness, repetitive supraventricular and ventricular arrhythmias and elevated cardiac/muscle enzymes were registered between 2016 and 2017 (Fig. 3). Serological tests for myositis-specific autoantibodies (MSAs) including anti-HMGCR, ANA and genetics for neuromuscular diseases were negative. Whole-body positron-emission-tomography computed-tomography (PET-CT) and pulmonary function tests were normal. Muscle biopsy showed fiber variability and cell necrosis compatible with immune-mediated, necrotizing myopathy. Prednisolone (75 mg/day) was initiated in January 2018 resulting in improved physical performance. In March 2018 methotrexate (MTX) (15–25 mg/week) was added and prednisolone tapered, resulting in continued clinical improvement and stable LVEF of 35%. In March 2019, while treated with MTX (20 mg/week) monotherapy, the patient experienced worsening of muscle weakness and dyspnea. Blood tests showed rising total CK (Fig. 3) and X-ray revealed pulmonary congestion. The condition improved transitorily on diuretics and increased MTX (25 mg/week). Six months later, the patient was brought to intensive care in cardiogenic shock due to decompensated severe biventricular failure. He was stabilized by inotropic support, diuretics, amiodarone, upregulation of CRT pace and glucocorticoids. TTE depicted biventricular hypofunction/dilatation (LVEF 10–15%), and a cardiac PET-CT (F-18-FDG/Rb-82) showed nonviable perfusion defect in the apex and lateral wall of the left ventricle (Fig. 4). A myocardial biopsy revealed mild to moderate hypertrophy and maturing replacement fibrosis with alcian-positive matrix indicating the presence of glycosaminoglycans as seen in early regeneration. Furthermore, endothelial proliferation and a few inflammatory cells were seen in the biopsy, suggesting a recent loss of myocytes (Fig. 5a and b). Cyclosporine (200 mg/day) and mycophenolate mofetil (2 g/day) were added to prednisolone (15 mg/day) to attenuate any inflammatory component. Despite stable peripheral muscle function, no convincing cardiac effect appeared. The combination of heart disease and myositis led to test for AMA in April 2020. AMA were present in unmeasurable high titers (>220 [<4 kIU/L]), supporting a diagnosis of cardiomyopathy related to AMA-associated inflammatory myositis (AMA-IM). In May 2020 rituximab therapy was started but unfortunately no cardiac improvement was achieved. Due to severe chronic renal impairment and ultimately liver failure the patient was not a candidate for heart transplantation. He died in cardiogenic and septic shock in July 2020.
DISCUSSION
AMA-IM is a rare and sparsely described disease entity occurring independently or along with other autoimmune conditions, especially PBC [1–3]. Two previous case series found AMA in 0.006 and 11.3%, respectively, of patients with inflammatory myopathy—a variation probably reflecting the limited amount of data in a rare entity [1, 2]. Cardiac involvement of AMA-IM is a rather new recognition only described by a few, previous case reports/series within the last decades [1–5].
Little is known about the clinical and histopathological phenotype of AMA-IM. In consistency with our observations, previous cases report polymorph cardiac involvement including arrhythmias, cardiomyopathy and heart failure as prominent clinical features [1–6], and muscle biopsies with varying degrees of inflammation, atrophy and fibrosis [1, 3–5].
Our patient developed PAF at age 35, which was perceived as a complication to Graves thyrotoxicosis. Retrospectively, PAF could have been an initial symptom of AMA-IM, as it continued despite normalization of thyroid function, and was succeeded by severe conduction abnormalities, rising total CK and decreasing muscle strength over the following years. Previous reports confirm that cardiac manifestations often precede muscle symptoms in AMA-IM, increasing the risk of misdiagnosing [1, 2]. In our case, the diagnostic process was further challenged by ambiguous test results as MSAs and ANA screening appeared normal, and neither imaging nor biopsies showed active inflammation. The muscle biopsy showed a necrotizing myopathy, which was not associated to statin as Atorvastatin was prescribed years after the onset of muscle involvement and no anti-HMGCR antibodies were detected. In the endomyocardial biopsy, myocarditis was not directly observed. However, the focal loss of myocytes and replacement with alcian positive material as part of the regenerative process suggests a recent damaging event, which may be myocarditis. The CMRI findings of LGE following cardiac arrest could be due to coronary thromboembolism or an inflammatory process of the myocardium. The former seems unlikely given the normal coronary arteries on the previous CAG. Hence, the initially sparse muscle symptoms and prolonged diagnostic process with step-wise exclusion of genetic -, other rheumatic-, ischemic- and malignant diseases, before AMA testing provided a final diagnosis, caused a treatment delay, which might in part explain the insufficient cardiac responsiveness to immune suppressants in our patient. However, a diminished cardiac versus muscular response to immunosuppressants in AMA-IM has been observed in previous cases, across genders, disease durations and drug types [1, 2, 4, 5]. Taken together, this might point to a need for more aggressive strategies to reverse the cardiac manifestations.
In conclusion, our case supports that cardiac involvement can be a severe complication in AMA-IM and emphasizes the importance of testing for AMA in etiologically unclarified inflammatory myopathies and cardiac failure. The lack of treatment effect on cardiac failure in our and previous cases may indicate that very early and aggressive management of heart involvement is necessary. However, future systematic studies are needed to clarify the optimal treatment strategies for this disease entity.
ACKNOWLEDGEMENTS
None.
CONFLICT OF INTEREST STATEMENT
P.H., N.W., K.R., R.P., P.H.A., T.H.LJ. and L.D. declare no conflicts of interest.
FUNDING
There was no funding for this case report.
ETHICAL APPROVAL
No approval from the Ethics Committee is required for this study according to Danish Legislation.
CONSENT
A written consent form has been fulfilled by the patient.
GUARANTOR
Louise Pyndt Diederichsen, MD, PhD. | Fatal | ReactionOutcome | CC BY-NC | 33732479 | 20,074,331 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Low birth weight baby'. | Paralytic ileus in the neonate as a rare complication of maternal methadone treatment-a case report.
Narcotic bowel syndrome is defined as worsening abdominal bloating and cramping with chronic opiate use, leading to paralytic ileus. This syndrome is common yet underreported in adults. However, there is no current evidence of such conditions in the newborn after exposure in utero to high doses of opiates. Our patient was a female indigenous preterm infant born to a mother on a high dose of methadone. On admission at the age of 12 h, she was found to have significant gastric distension. Initial abdominal X-ray showed a large gastric bubble with little evidence of rectal gas. Malrotation was suspected and surgical intervention was discussed. However, repeat abdominal X-ray, ultrasound and upper Gastrointestinal series were found to be normal and without acute findings. Thus, surgery was avoided. The gastric distension resolved spontaneously. She never required opiate therapy for neonatal abstinence syndrome. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after removal of maternal methadone, we suspect this baby had neonatal narcotic bowel syndrome. This has never been reported in the literature and is a unique finding. Given the lack of current reports, further observations for this syndrome should be conducted.
INTRODUCTION
Opioids are potent analgesic agents used to treat severe pain that is both acute and chronic in nature [1]. Common side effects include constipation and bowel dysfunction [1]. This is a result of action of opioids on receptors that line the gastrointestinal tract [1]. Chronic opiate use could lead to the bowel dysfunction, constipations or paralytic ileus [2]. In the pregnant population, illicit opioid use is found in approximately 0.1% of all pregnancies [3]. Currently, the recommended pharmacotherapy for opioid dependency in the antenatal period is methadone, which was found to diminish illicit use [3–5]. The most common side effect of maternal methadone and opiate use is neonatal abstinence syndrome (NAS), a set of signs and symptoms related to nervous system dysfunction that increases morbidity and prolongs NICU stay [3, 5]. In the available literature, we did not find reports describing early-onset gastrointestinal dysfunction in the neonates exposed to opiates and methadone in utero. In the given case report, we present a neonate with physical signs and radiologic evidence of ileus secondary to maternal methadone ingestion.
CASE REPORT
This baby girl was born via home spontaneous vaginal delivery at approximately 32 weeks to a mother with no prenatal care or ultrasounds. She was HIV negative, and the remainder of serology results and GBS status were unknown. Subsequent postnatal screening was negative. The mother had a remote history of illicit drug use and was on maintenance therapy with methadone 100 mg/day throughout pregnancy. She was taking it as prescribed, which was confirmed by home visits. She had no other illicit substance use. She did intermittently smoke cigarettes and marijuana during the first trimester of pregnancy. She did not specify any alcohol use. Baby was born at home by spontaneous precipitous delivery and brought to a peripheral hospital by ambulance for further care. Her birth weight was 1392 g. Secondary to worsening respiratory distress, she was intubated and transferred to our tertiary care center.
On admission, she was screened for infection and started on empiric antibiotics. Blood cultures were negative. Baby was clinically stable but was found to have abdominal distension and was nil per os. The initial abdominal X-ray (Fig. 1a) showed massive gastric distension with minimal gas pattern in the rest of the gut. There was no concern of duodenal atresia given the gas pattern; however, gastric outlet obstruction or malrotation could not be ruled out. Intermittent NG suctioning was then applied for gastric decompression and only air was aspirated. No vomiting or bilious aspirates were noted. An abdominal X-ray was repeated an hour later, showing the stomach had been deflated with air again being present in the distal transverse, descending and rectosigmoid colon (Fig. 1b). A further X-ray was done 2 h later showing reaccumulation of air in the stomach and bowel loops distended throughout the left abdomen (Fig. 1c).
Figure 1 (a–c) Progression of the abdominal X-ray from an appearance of gastric outlet obstruction (a) to fairly decompressed (b) to a complete pattern of distension throughout the stomach, small and large bowels (c).
Therefore, an abdominal ultrasound was conducted to rule out malrotation and assess the gut vasculature. The superior mesenteric artery and vein were found to be in normal orientation. Furthermore, pediatric surgery was promptly consulted after the ultrasound and saw no acute need for exploratory laparotomy. They recommended an upper Gastrointestinal (GI) series after 2 days of gastric decompression. In the meantime, the patient was hemodynamically stable. The upper GI series showed no acute obstruction or other significant findings (Fig. 2a–d). The abdominal distension resolved within 72 h of life at which time she passed meconium. Feeds were started with preterm formula at the same time and were tolerated well. No further abdominal foci was identified. She was successfully extubated on Day 7 of life and off respiratory support by Day 9 of life. Screening head ultrasounds and chest X-rays were normal. The infant had no clinical signs of NAS. Feeds were progressed over the subsequent 3 weeks on standard formula prior to discharge after a total of 6 weeks in NICU.
Figure 2 (a–c) Normal upper GI series; (d, e) normal upper GI series and final X-ray showing normal distribution of contrast throughout the small and large bowel.
DISCUSSION
For more than 30 years, methadone has been used as a first-line medication for opioid substitution therapy during pregnancy [5]. Despite the strong evidence supporting the use of methadone in pregnancy, methadone use is not without risk or side effects [5, 6]. Methadone does not only cross the placental barrier but is also retained by the placenta in a substantial amount [4]. There is not enough data describing fetal opioid elimination, however, placental inactivation of methadone is significantly lower than that of the maternal liver [6–8]. The elimination half-life of methadone in an opioid-tolerant patient is approximately 24 h; and in neonates, it could be as high as 40–55 h [6, 7]. The extended elimination half-life in neonates contributes to higher mg per kg-based dose [6].
There is well-documented evidence of delay of feeding onset and attaining full feeds in neonates with NAS or exposed to morphine in the NICU for analgesia [9, 10]. Fortunately, these effects are transient with no acquired GI complications [7, 8]. Our patient was off respiratory support in 9 days. Her infectious status was negative. However, abdominal distension persisted for 72 h. Her mother did not use other substances late in pregnancy other than methadone. Given that the neonate reported in this case study did not show signs of NAS, it seems less likely that we can contribute her clinical picture of ileus to her methadone exposure. However, the preterm neonates have lower rates of NAS compared to term babies [8], so she may not have displayed symptoms of withdrawal due to her prematurity. This association may well be due to the challenges of assessment of NAS in preterm infants and a lack of a validated scoring system specifically designed for this population [9]. It is important to consider maternal substance use when interpreting abdominal films and clinical signs of a surgical abdomen. These findings may help reduce the need for exploratory laparotomy in neonates presenting with a query of a surgical abdomen, if maternal substance use history is known.
Interestingly, there was a case report of an infant in Italy who experienced similar paralytic ileus after treatment with fentanyl for procedural sedation while ventilated [10]. Although the exposure was of a different nature, it is important nevertheless to know that any opioid derivative has the capacity to induce ileus in the neonate, whether prenatal or postnatal. Furthermore, another preterm infant whose mother was taking clonazepam, a benzodiazepine for epilepsy, was also born with concern of a paralytic ileus [10]. This adds further support to the argument that neurologically depressing agents use by a mother during pregnancy, such as opioids and benzodiazepines, must be considered when observing an infant with radiological and clinical signs of an obstructive pathology before advancing that neonate for laparotomy.
In conclusion, the given neonate was born premature after significant in utero exposure to methadone and was thought to have a malrotation on imaging. After ruling out a surgical cause of obstruction, the only factor that could be associated with such significant ileus was determined to be maternal methadone consumption. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after 72 h, we suspect this baby had paralytic ileus secondary to maternal methadone treatment. This has never been reported in the literature and is a unique finding. Hence, this correlation is a reminder to neonatology decision makers that maternal substance use may be a significant considering factor when sending a patient with small bowel obstruction to the operating theater. Given the lack of current reports, further surveillance for this phenomenon should be conducted.
CONFLICT OF INTEREST
None declared.
FUNDING
No sources of funding were used.
ETHICS APPROVAL
Ethics approval for said case report was waived. Parental consent was gained prior to creating this manuscript.
CONSENT
All images and information presented about the given minor were used with informed consent from the individual’s legal guardian. All images were anonymized.
GUARANTOR
Veronica Mugarab Samedi is a guarantor for this publication.
ACKNOWLEDGEMENTS
Not applicable. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33732483 | 19,971,945 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Narcotic bowel syndrome'. | Paralytic ileus in the neonate as a rare complication of maternal methadone treatment-a case report.
Narcotic bowel syndrome is defined as worsening abdominal bloating and cramping with chronic opiate use, leading to paralytic ileus. This syndrome is common yet underreported in adults. However, there is no current evidence of such conditions in the newborn after exposure in utero to high doses of opiates. Our patient was a female indigenous preterm infant born to a mother on a high dose of methadone. On admission at the age of 12 h, she was found to have significant gastric distension. Initial abdominal X-ray showed a large gastric bubble with little evidence of rectal gas. Malrotation was suspected and surgical intervention was discussed. However, repeat abdominal X-ray, ultrasound and upper Gastrointestinal series were found to be normal and without acute findings. Thus, surgery was avoided. The gastric distension resolved spontaneously. She never required opiate therapy for neonatal abstinence syndrome. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after removal of maternal methadone, we suspect this baby had neonatal narcotic bowel syndrome. This has never been reported in the literature and is a unique finding. Given the lack of current reports, further observations for this syndrome should be conducted.
INTRODUCTION
Opioids are potent analgesic agents used to treat severe pain that is both acute and chronic in nature [1]. Common side effects include constipation and bowel dysfunction [1]. This is a result of action of opioids on receptors that line the gastrointestinal tract [1]. Chronic opiate use could lead to the bowel dysfunction, constipations or paralytic ileus [2]. In the pregnant population, illicit opioid use is found in approximately 0.1% of all pregnancies [3]. Currently, the recommended pharmacotherapy for opioid dependency in the antenatal period is methadone, which was found to diminish illicit use [3–5]. The most common side effect of maternal methadone and opiate use is neonatal abstinence syndrome (NAS), a set of signs and symptoms related to nervous system dysfunction that increases morbidity and prolongs NICU stay [3, 5]. In the available literature, we did not find reports describing early-onset gastrointestinal dysfunction in the neonates exposed to opiates and methadone in utero. In the given case report, we present a neonate with physical signs and radiologic evidence of ileus secondary to maternal methadone ingestion.
CASE REPORT
This baby girl was born via home spontaneous vaginal delivery at approximately 32 weeks to a mother with no prenatal care or ultrasounds. She was HIV negative, and the remainder of serology results and GBS status were unknown. Subsequent postnatal screening was negative. The mother had a remote history of illicit drug use and was on maintenance therapy with methadone 100 mg/day throughout pregnancy. She was taking it as prescribed, which was confirmed by home visits. She had no other illicit substance use. She did intermittently smoke cigarettes and marijuana during the first trimester of pregnancy. She did not specify any alcohol use. Baby was born at home by spontaneous precipitous delivery and brought to a peripheral hospital by ambulance for further care. Her birth weight was 1392 g. Secondary to worsening respiratory distress, she was intubated and transferred to our tertiary care center.
On admission, she was screened for infection and started on empiric antibiotics. Blood cultures were negative. Baby was clinically stable but was found to have abdominal distension and was nil per os. The initial abdominal X-ray (Fig. 1a) showed massive gastric distension with minimal gas pattern in the rest of the gut. There was no concern of duodenal atresia given the gas pattern; however, gastric outlet obstruction or malrotation could not be ruled out. Intermittent NG suctioning was then applied for gastric decompression and only air was aspirated. No vomiting or bilious aspirates were noted. An abdominal X-ray was repeated an hour later, showing the stomach had been deflated with air again being present in the distal transverse, descending and rectosigmoid colon (Fig. 1b). A further X-ray was done 2 h later showing reaccumulation of air in the stomach and bowel loops distended throughout the left abdomen (Fig. 1c).
Figure 1 (a–c) Progression of the abdominal X-ray from an appearance of gastric outlet obstruction (a) to fairly decompressed (b) to a complete pattern of distension throughout the stomach, small and large bowels (c).
Therefore, an abdominal ultrasound was conducted to rule out malrotation and assess the gut vasculature. The superior mesenteric artery and vein were found to be in normal orientation. Furthermore, pediatric surgery was promptly consulted after the ultrasound and saw no acute need for exploratory laparotomy. They recommended an upper Gastrointestinal (GI) series after 2 days of gastric decompression. In the meantime, the patient was hemodynamically stable. The upper GI series showed no acute obstruction or other significant findings (Fig. 2a–d). The abdominal distension resolved within 72 h of life at which time she passed meconium. Feeds were started with preterm formula at the same time and were tolerated well. No further abdominal foci was identified. She was successfully extubated on Day 7 of life and off respiratory support by Day 9 of life. Screening head ultrasounds and chest X-rays were normal. The infant had no clinical signs of NAS. Feeds were progressed over the subsequent 3 weeks on standard formula prior to discharge after a total of 6 weeks in NICU.
Figure 2 (a–c) Normal upper GI series; (d, e) normal upper GI series and final X-ray showing normal distribution of contrast throughout the small and large bowel.
DISCUSSION
For more than 30 years, methadone has been used as a first-line medication for opioid substitution therapy during pregnancy [5]. Despite the strong evidence supporting the use of methadone in pregnancy, methadone use is not without risk or side effects [5, 6]. Methadone does not only cross the placental barrier but is also retained by the placenta in a substantial amount [4]. There is not enough data describing fetal opioid elimination, however, placental inactivation of methadone is significantly lower than that of the maternal liver [6–8]. The elimination half-life of methadone in an opioid-tolerant patient is approximately 24 h; and in neonates, it could be as high as 40–55 h [6, 7]. The extended elimination half-life in neonates contributes to higher mg per kg-based dose [6].
There is well-documented evidence of delay of feeding onset and attaining full feeds in neonates with NAS or exposed to morphine in the NICU for analgesia [9, 10]. Fortunately, these effects are transient with no acquired GI complications [7, 8]. Our patient was off respiratory support in 9 days. Her infectious status was negative. However, abdominal distension persisted for 72 h. Her mother did not use other substances late in pregnancy other than methadone. Given that the neonate reported in this case study did not show signs of NAS, it seems less likely that we can contribute her clinical picture of ileus to her methadone exposure. However, the preterm neonates have lower rates of NAS compared to term babies [8], so she may not have displayed symptoms of withdrawal due to her prematurity. This association may well be due to the challenges of assessment of NAS in preterm infants and a lack of a validated scoring system specifically designed for this population [9]. It is important to consider maternal substance use when interpreting abdominal films and clinical signs of a surgical abdomen. These findings may help reduce the need for exploratory laparotomy in neonates presenting with a query of a surgical abdomen, if maternal substance use history is known.
Interestingly, there was a case report of an infant in Italy who experienced similar paralytic ileus after treatment with fentanyl for procedural sedation while ventilated [10]. Although the exposure was of a different nature, it is important nevertheless to know that any opioid derivative has the capacity to induce ileus in the neonate, whether prenatal or postnatal. Furthermore, another preterm infant whose mother was taking clonazepam, a benzodiazepine for epilepsy, was also born with concern of a paralytic ileus [10]. This adds further support to the argument that neurologically depressing agents use by a mother during pregnancy, such as opioids and benzodiazepines, must be considered when observing an infant with radiological and clinical signs of an obstructive pathology before advancing that neonate for laparotomy.
In conclusion, the given neonate was born premature after significant in utero exposure to methadone and was thought to have a malrotation on imaging. After ruling out a surgical cause of obstruction, the only factor that could be associated with such significant ileus was determined to be maternal methadone consumption. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after 72 h, we suspect this baby had paralytic ileus secondary to maternal methadone treatment. This has never been reported in the literature and is a unique finding. Hence, this correlation is a reminder to neonatology decision makers that maternal substance use may be a significant considering factor when sending a patient with small bowel obstruction to the operating theater. Given the lack of current reports, further surveillance for this phenomenon should be conducted.
CONFLICT OF INTEREST
None declared.
FUNDING
No sources of funding were used.
ETHICS APPROVAL
Ethics approval for said case report was waived. Parental consent was gained prior to creating this manuscript.
CONSENT
All images and information presented about the given minor were used with informed consent from the individual’s legal guardian. All images were anonymized.
GUARANTOR
Veronica Mugarab Samedi is a guarantor for this publication.
ACKNOWLEDGEMENTS
Not applicable. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33732483 | 19,374,172 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neonatal respiratory distress'. | Paralytic ileus in the neonate as a rare complication of maternal methadone treatment-a case report.
Narcotic bowel syndrome is defined as worsening abdominal bloating and cramping with chronic opiate use, leading to paralytic ileus. This syndrome is common yet underreported in adults. However, there is no current evidence of such conditions in the newborn after exposure in utero to high doses of opiates. Our patient was a female indigenous preterm infant born to a mother on a high dose of methadone. On admission at the age of 12 h, she was found to have significant gastric distension. Initial abdominal X-ray showed a large gastric bubble with little evidence of rectal gas. Malrotation was suspected and surgical intervention was discussed. However, repeat abdominal X-ray, ultrasound and upper Gastrointestinal series were found to be normal and without acute findings. Thus, surgery was avoided. The gastric distension resolved spontaneously. She never required opiate therapy for neonatal abstinence syndrome. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after removal of maternal methadone, we suspect this baby had neonatal narcotic bowel syndrome. This has never been reported in the literature and is a unique finding. Given the lack of current reports, further observations for this syndrome should be conducted.
INTRODUCTION
Opioids are potent analgesic agents used to treat severe pain that is both acute and chronic in nature [1]. Common side effects include constipation and bowel dysfunction [1]. This is a result of action of opioids on receptors that line the gastrointestinal tract [1]. Chronic opiate use could lead to the bowel dysfunction, constipations or paralytic ileus [2]. In the pregnant population, illicit opioid use is found in approximately 0.1% of all pregnancies [3]. Currently, the recommended pharmacotherapy for opioid dependency in the antenatal period is methadone, which was found to diminish illicit use [3–5]. The most common side effect of maternal methadone and opiate use is neonatal abstinence syndrome (NAS), a set of signs and symptoms related to nervous system dysfunction that increases morbidity and prolongs NICU stay [3, 5]. In the available literature, we did not find reports describing early-onset gastrointestinal dysfunction in the neonates exposed to opiates and methadone in utero. In the given case report, we present a neonate with physical signs and radiologic evidence of ileus secondary to maternal methadone ingestion.
CASE REPORT
This baby girl was born via home spontaneous vaginal delivery at approximately 32 weeks to a mother with no prenatal care or ultrasounds. She was HIV negative, and the remainder of serology results and GBS status were unknown. Subsequent postnatal screening was negative. The mother had a remote history of illicit drug use and was on maintenance therapy with methadone 100 mg/day throughout pregnancy. She was taking it as prescribed, which was confirmed by home visits. She had no other illicit substance use. She did intermittently smoke cigarettes and marijuana during the first trimester of pregnancy. She did not specify any alcohol use. Baby was born at home by spontaneous precipitous delivery and brought to a peripheral hospital by ambulance for further care. Her birth weight was 1392 g. Secondary to worsening respiratory distress, she was intubated and transferred to our tertiary care center.
On admission, she was screened for infection and started on empiric antibiotics. Blood cultures were negative. Baby was clinically stable but was found to have abdominal distension and was nil per os. The initial abdominal X-ray (Fig. 1a) showed massive gastric distension with minimal gas pattern in the rest of the gut. There was no concern of duodenal atresia given the gas pattern; however, gastric outlet obstruction or malrotation could not be ruled out. Intermittent NG suctioning was then applied for gastric decompression and only air was aspirated. No vomiting or bilious aspirates were noted. An abdominal X-ray was repeated an hour later, showing the stomach had been deflated with air again being present in the distal transverse, descending and rectosigmoid colon (Fig. 1b). A further X-ray was done 2 h later showing reaccumulation of air in the stomach and bowel loops distended throughout the left abdomen (Fig. 1c).
Figure 1 (a–c) Progression of the abdominal X-ray from an appearance of gastric outlet obstruction (a) to fairly decompressed (b) to a complete pattern of distension throughout the stomach, small and large bowels (c).
Therefore, an abdominal ultrasound was conducted to rule out malrotation and assess the gut vasculature. The superior mesenteric artery and vein were found to be in normal orientation. Furthermore, pediatric surgery was promptly consulted after the ultrasound and saw no acute need for exploratory laparotomy. They recommended an upper Gastrointestinal (GI) series after 2 days of gastric decompression. In the meantime, the patient was hemodynamically stable. The upper GI series showed no acute obstruction or other significant findings (Fig. 2a–d). The abdominal distension resolved within 72 h of life at which time she passed meconium. Feeds were started with preterm formula at the same time and were tolerated well. No further abdominal foci was identified. She was successfully extubated on Day 7 of life and off respiratory support by Day 9 of life. Screening head ultrasounds and chest X-rays were normal. The infant had no clinical signs of NAS. Feeds were progressed over the subsequent 3 weeks on standard formula prior to discharge after a total of 6 weeks in NICU.
Figure 2 (a–c) Normal upper GI series; (d, e) normal upper GI series and final X-ray showing normal distribution of contrast throughout the small and large bowel.
DISCUSSION
For more than 30 years, methadone has been used as a first-line medication for opioid substitution therapy during pregnancy [5]. Despite the strong evidence supporting the use of methadone in pregnancy, methadone use is not without risk or side effects [5, 6]. Methadone does not only cross the placental barrier but is also retained by the placenta in a substantial amount [4]. There is not enough data describing fetal opioid elimination, however, placental inactivation of methadone is significantly lower than that of the maternal liver [6–8]. The elimination half-life of methadone in an opioid-tolerant patient is approximately 24 h; and in neonates, it could be as high as 40–55 h [6, 7]. The extended elimination half-life in neonates contributes to higher mg per kg-based dose [6].
There is well-documented evidence of delay of feeding onset and attaining full feeds in neonates with NAS or exposed to morphine in the NICU for analgesia [9, 10]. Fortunately, these effects are transient with no acquired GI complications [7, 8]. Our patient was off respiratory support in 9 days. Her infectious status was negative. However, abdominal distension persisted for 72 h. Her mother did not use other substances late in pregnancy other than methadone. Given that the neonate reported in this case study did not show signs of NAS, it seems less likely that we can contribute her clinical picture of ileus to her methadone exposure. However, the preterm neonates have lower rates of NAS compared to term babies [8], so she may not have displayed symptoms of withdrawal due to her prematurity. This association may well be due to the challenges of assessment of NAS in preterm infants and a lack of a validated scoring system specifically designed for this population [9]. It is important to consider maternal substance use when interpreting abdominal films and clinical signs of a surgical abdomen. These findings may help reduce the need for exploratory laparotomy in neonates presenting with a query of a surgical abdomen, if maternal substance use history is known.
Interestingly, there was a case report of an infant in Italy who experienced similar paralytic ileus after treatment with fentanyl for procedural sedation while ventilated [10]. Although the exposure was of a different nature, it is important nevertheless to know that any opioid derivative has the capacity to induce ileus in the neonate, whether prenatal or postnatal. Furthermore, another preterm infant whose mother was taking clonazepam, a benzodiazepine for epilepsy, was also born with concern of a paralytic ileus [10]. This adds further support to the argument that neurologically depressing agents use by a mother during pregnancy, such as opioids and benzodiazepines, must be considered when observing an infant with radiological and clinical signs of an obstructive pathology before advancing that neonate for laparotomy.
In conclusion, the given neonate was born premature after significant in utero exposure to methadone and was thought to have a malrotation on imaging. After ruling out a surgical cause of obstruction, the only factor that could be associated with such significant ileus was determined to be maternal methadone consumption. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after 72 h, we suspect this baby had paralytic ileus secondary to maternal methadone treatment. This has never been reported in the literature and is a unique finding. Hence, this correlation is a reminder to neonatology decision makers that maternal substance use may be a significant considering factor when sending a patient with small bowel obstruction to the operating theater. Given the lack of current reports, further surveillance for this phenomenon should be conducted.
CONFLICT OF INTEREST
None declared.
FUNDING
No sources of funding were used.
ETHICS APPROVAL
Ethics approval for said case report was waived. Parental consent was gained prior to creating this manuscript.
CONSENT
All images and information presented about the given minor were used with informed consent from the individual’s legal guardian. All images were anonymized.
GUARANTOR
Veronica Mugarab Samedi is a guarantor for this publication.
ACKNOWLEDGEMENTS
Not applicable. | CANNABIS SATIVA SUBSP. INDICA TOP, METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33732483 | 19,903,447 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory distress'. | Paralytic ileus in the neonate as a rare complication of maternal methadone treatment-a case report.
Narcotic bowel syndrome is defined as worsening abdominal bloating and cramping with chronic opiate use, leading to paralytic ileus. This syndrome is common yet underreported in adults. However, there is no current evidence of such conditions in the newborn after exposure in utero to high doses of opiates. Our patient was a female indigenous preterm infant born to a mother on a high dose of methadone. On admission at the age of 12 h, she was found to have significant gastric distension. Initial abdominal X-ray showed a large gastric bubble with little evidence of rectal gas. Malrotation was suspected and surgical intervention was discussed. However, repeat abdominal X-ray, ultrasound and upper Gastrointestinal series were found to be normal and without acute findings. Thus, surgery was avoided. The gastric distension resolved spontaneously. She never required opiate therapy for neonatal abstinence syndrome. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after removal of maternal methadone, we suspect this baby had neonatal narcotic bowel syndrome. This has never been reported in the literature and is a unique finding. Given the lack of current reports, further observations for this syndrome should be conducted.
INTRODUCTION
Opioids are potent analgesic agents used to treat severe pain that is both acute and chronic in nature [1]. Common side effects include constipation and bowel dysfunction [1]. This is a result of action of opioids on receptors that line the gastrointestinal tract [1]. Chronic opiate use could lead to the bowel dysfunction, constipations or paralytic ileus [2]. In the pregnant population, illicit opioid use is found in approximately 0.1% of all pregnancies [3]. Currently, the recommended pharmacotherapy for opioid dependency in the antenatal period is methadone, which was found to diminish illicit use [3–5]. The most common side effect of maternal methadone and opiate use is neonatal abstinence syndrome (NAS), a set of signs and symptoms related to nervous system dysfunction that increases morbidity and prolongs NICU stay [3, 5]. In the available literature, we did not find reports describing early-onset gastrointestinal dysfunction in the neonates exposed to opiates and methadone in utero. In the given case report, we present a neonate with physical signs and radiologic evidence of ileus secondary to maternal methadone ingestion.
CASE REPORT
This baby girl was born via home spontaneous vaginal delivery at approximately 32 weeks to a mother with no prenatal care or ultrasounds. She was HIV negative, and the remainder of serology results and GBS status were unknown. Subsequent postnatal screening was negative. The mother had a remote history of illicit drug use and was on maintenance therapy with methadone 100 mg/day throughout pregnancy. She was taking it as prescribed, which was confirmed by home visits. She had no other illicit substance use. She did intermittently smoke cigarettes and marijuana during the first trimester of pregnancy. She did not specify any alcohol use. Baby was born at home by spontaneous precipitous delivery and brought to a peripheral hospital by ambulance for further care. Her birth weight was 1392 g. Secondary to worsening respiratory distress, she was intubated and transferred to our tertiary care center.
On admission, she was screened for infection and started on empiric antibiotics. Blood cultures were negative. Baby was clinically stable but was found to have abdominal distension and was nil per os. The initial abdominal X-ray (Fig. 1a) showed massive gastric distension with minimal gas pattern in the rest of the gut. There was no concern of duodenal atresia given the gas pattern; however, gastric outlet obstruction or malrotation could not be ruled out. Intermittent NG suctioning was then applied for gastric decompression and only air was aspirated. No vomiting or bilious aspirates were noted. An abdominal X-ray was repeated an hour later, showing the stomach had been deflated with air again being present in the distal transverse, descending and rectosigmoid colon (Fig. 1b). A further X-ray was done 2 h later showing reaccumulation of air in the stomach and bowel loops distended throughout the left abdomen (Fig. 1c).
Figure 1 (a–c) Progression of the abdominal X-ray from an appearance of gastric outlet obstruction (a) to fairly decompressed (b) to a complete pattern of distension throughout the stomach, small and large bowels (c).
Therefore, an abdominal ultrasound was conducted to rule out malrotation and assess the gut vasculature. The superior mesenteric artery and vein were found to be in normal orientation. Furthermore, pediatric surgery was promptly consulted after the ultrasound and saw no acute need for exploratory laparotomy. They recommended an upper Gastrointestinal (GI) series after 2 days of gastric decompression. In the meantime, the patient was hemodynamically stable. The upper GI series showed no acute obstruction or other significant findings (Fig. 2a–d). The abdominal distension resolved within 72 h of life at which time she passed meconium. Feeds were started with preterm formula at the same time and were tolerated well. No further abdominal foci was identified. She was successfully extubated on Day 7 of life and off respiratory support by Day 9 of life. Screening head ultrasounds and chest X-rays were normal. The infant had no clinical signs of NAS. Feeds were progressed over the subsequent 3 weeks on standard formula prior to discharge after a total of 6 weeks in NICU.
Figure 2 (a–c) Normal upper GI series; (d, e) normal upper GI series and final X-ray showing normal distribution of contrast throughout the small and large bowel.
DISCUSSION
For more than 30 years, methadone has been used as a first-line medication for opioid substitution therapy during pregnancy [5]. Despite the strong evidence supporting the use of methadone in pregnancy, methadone use is not without risk or side effects [5, 6]. Methadone does not only cross the placental barrier but is also retained by the placenta in a substantial amount [4]. There is not enough data describing fetal opioid elimination, however, placental inactivation of methadone is significantly lower than that of the maternal liver [6–8]. The elimination half-life of methadone in an opioid-tolerant patient is approximately 24 h; and in neonates, it could be as high as 40–55 h [6, 7]. The extended elimination half-life in neonates contributes to higher mg per kg-based dose [6].
There is well-documented evidence of delay of feeding onset and attaining full feeds in neonates with NAS or exposed to morphine in the NICU for analgesia [9, 10]. Fortunately, these effects are transient with no acquired GI complications [7, 8]. Our patient was off respiratory support in 9 days. Her infectious status was negative. However, abdominal distension persisted for 72 h. Her mother did not use other substances late in pregnancy other than methadone. Given that the neonate reported in this case study did not show signs of NAS, it seems less likely that we can contribute her clinical picture of ileus to her methadone exposure. However, the preterm neonates have lower rates of NAS compared to term babies [8], so she may not have displayed symptoms of withdrawal due to her prematurity. This association may well be due to the challenges of assessment of NAS in preterm infants and a lack of a validated scoring system specifically designed for this population [9]. It is important to consider maternal substance use when interpreting abdominal films and clinical signs of a surgical abdomen. These findings may help reduce the need for exploratory laparotomy in neonates presenting with a query of a surgical abdomen, if maternal substance use history is known.
Interestingly, there was a case report of an infant in Italy who experienced similar paralytic ileus after treatment with fentanyl for procedural sedation while ventilated [10]. Although the exposure was of a different nature, it is important nevertheless to know that any opioid derivative has the capacity to induce ileus in the neonate, whether prenatal or postnatal. Furthermore, another preterm infant whose mother was taking clonazepam, a benzodiazepine for epilepsy, was also born with concern of a paralytic ileus [10]. This adds further support to the argument that neurologically depressing agents use by a mother during pregnancy, such as opioids and benzodiazepines, must be considered when observing an infant with radiological and clinical signs of an obstructive pathology before advancing that neonate for laparotomy.
In conclusion, the given neonate was born premature after significant in utero exposure to methadone and was thought to have a malrotation on imaging. After ruling out a surgical cause of obstruction, the only factor that could be associated with such significant ileus was determined to be maternal methadone consumption. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after 72 h, we suspect this baby had paralytic ileus secondary to maternal methadone treatment. This has never been reported in the literature and is a unique finding. Hence, this correlation is a reminder to neonatology decision makers that maternal substance use may be a significant considering factor when sending a patient with small bowel obstruction to the operating theater. Given the lack of current reports, further surveillance for this phenomenon should be conducted.
CONFLICT OF INTEREST
None declared.
FUNDING
No sources of funding were used.
ETHICS APPROVAL
Ethics approval for said case report was waived. Parental consent was gained prior to creating this manuscript.
CONSENT
All images and information presented about the given minor were used with informed consent from the individual’s legal guardian. All images were anonymized.
GUARANTOR
Veronica Mugarab Samedi is a guarantor for this publication.
ACKNOWLEDGEMENTS
Not applicable. | METHADONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33732483 | 19,374,172 | 2021-03 |
What was the administration route of drug 'CANNABIS SATIVA SUBSP. INDICA TOP'? | Paralytic ileus in the neonate as a rare complication of maternal methadone treatment-a case report.
Narcotic bowel syndrome is defined as worsening abdominal bloating and cramping with chronic opiate use, leading to paralytic ileus. This syndrome is common yet underreported in adults. However, there is no current evidence of such conditions in the newborn after exposure in utero to high doses of opiates. Our patient was a female indigenous preterm infant born to a mother on a high dose of methadone. On admission at the age of 12 h, she was found to have significant gastric distension. Initial abdominal X-ray showed a large gastric bubble with little evidence of rectal gas. Malrotation was suspected and surgical intervention was discussed. However, repeat abdominal X-ray, ultrasound and upper Gastrointestinal series were found to be normal and without acute findings. Thus, surgery was avoided. The gastric distension resolved spontaneously. She never required opiate therapy for neonatal abstinence syndrome. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after removal of maternal methadone, we suspect this baby had neonatal narcotic bowel syndrome. This has never been reported in the literature and is a unique finding. Given the lack of current reports, further observations for this syndrome should be conducted.
INTRODUCTION
Opioids are potent analgesic agents used to treat severe pain that is both acute and chronic in nature [1]. Common side effects include constipation and bowel dysfunction [1]. This is a result of action of opioids on receptors that line the gastrointestinal tract [1]. Chronic opiate use could lead to the bowel dysfunction, constipations or paralytic ileus [2]. In the pregnant population, illicit opioid use is found in approximately 0.1% of all pregnancies [3]. Currently, the recommended pharmacotherapy for opioid dependency in the antenatal period is methadone, which was found to diminish illicit use [3–5]. The most common side effect of maternal methadone and opiate use is neonatal abstinence syndrome (NAS), a set of signs and symptoms related to nervous system dysfunction that increases morbidity and prolongs NICU stay [3, 5]. In the available literature, we did not find reports describing early-onset gastrointestinal dysfunction in the neonates exposed to opiates and methadone in utero. In the given case report, we present a neonate with physical signs and radiologic evidence of ileus secondary to maternal methadone ingestion.
CASE REPORT
This baby girl was born via home spontaneous vaginal delivery at approximately 32 weeks to a mother with no prenatal care or ultrasounds. She was HIV negative, and the remainder of serology results and GBS status were unknown. Subsequent postnatal screening was negative. The mother had a remote history of illicit drug use and was on maintenance therapy with methadone 100 mg/day throughout pregnancy. She was taking it as prescribed, which was confirmed by home visits. She had no other illicit substance use. She did intermittently smoke cigarettes and marijuana during the first trimester of pregnancy. She did not specify any alcohol use. Baby was born at home by spontaneous precipitous delivery and brought to a peripheral hospital by ambulance for further care. Her birth weight was 1392 g. Secondary to worsening respiratory distress, she was intubated and transferred to our tertiary care center.
On admission, she was screened for infection and started on empiric antibiotics. Blood cultures were negative. Baby was clinically stable but was found to have abdominal distension and was nil per os. The initial abdominal X-ray (Fig. 1a) showed massive gastric distension with minimal gas pattern in the rest of the gut. There was no concern of duodenal atresia given the gas pattern; however, gastric outlet obstruction or malrotation could not be ruled out. Intermittent NG suctioning was then applied for gastric decompression and only air was aspirated. No vomiting or bilious aspirates were noted. An abdominal X-ray was repeated an hour later, showing the stomach had been deflated with air again being present in the distal transverse, descending and rectosigmoid colon (Fig. 1b). A further X-ray was done 2 h later showing reaccumulation of air in the stomach and bowel loops distended throughout the left abdomen (Fig. 1c).
Figure 1 (a–c) Progression of the abdominal X-ray from an appearance of gastric outlet obstruction (a) to fairly decompressed (b) to a complete pattern of distension throughout the stomach, small and large bowels (c).
Therefore, an abdominal ultrasound was conducted to rule out malrotation and assess the gut vasculature. The superior mesenteric artery and vein were found to be in normal orientation. Furthermore, pediatric surgery was promptly consulted after the ultrasound and saw no acute need for exploratory laparotomy. They recommended an upper Gastrointestinal (GI) series after 2 days of gastric decompression. In the meantime, the patient was hemodynamically stable. The upper GI series showed no acute obstruction or other significant findings (Fig. 2a–d). The abdominal distension resolved within 72 h of life at which time she passed meconium. Feeds were started with preterm formula at the same time and were tolerated well. No further abdominal foci was identified. She was successfully extubated on Day 7 of life and off respiratory support by Day 9 of life. Screening head ultrasounds and chest X-rays were normal. The infant had no clinical signs of NAS. Feeds were progressed over the subsequent 3 weeks on standard formula prior to discharge after a total of 6 weeks in NICU.
Figure 2 (a–c) Normal upper GI series; (d, e) normal upper GI series and final X-ray showing normal distribution of contrast throughout the small and large bowel.
DISCUSSION
For more than 30 years, methadone has been used as a first-line medication for opioid substitution therapy during pregnancy [5]. Despite the strong evidence supporting the use of methadone in pregnancy, methadone use is not without risk or side effects [5, 6]. Methadone does not only cross the placental barrier but is also retained by the placenta in a substantial amount [4]. There is not enough data describing fetal opioid elimination, however, placental inactivation of methadone is significantly lower than that of the maternal liver [6–8]. The elimination half-life of methadone in an opioid-tolerant patient is approximately 24 h; and in neonates, it could be as high as 40–55 h [6, 7]. The extended elimination half-life in neonates contributes to higher mg per kg-based dose [6].
There is well-documented evidence of delay of feeding onset and attaining full feeds in neonates with NAS or exposed to morphine in the NICU for analgesia [9, 10]. Fortunately, these effects are transient with no acquired GI complications [7, 8]. Our patient was off respiratory support in 9 days. Her infectious status was negative. However, abdominal distension persisted for 72 h. Her mother did not use other substances late in pregnancy other than methadone. Given that the neonate reported in this case study did not show signs of NAS, it seems less likely that we can contribute her clinical picture of ileus to her methadone exposure. However, the preterm neonates have lower rates of NAS compared to term babies [8], so she may not have displayed symptoms of withdrawal due to her prematurity. This association may well be due to the challenges of assessment of NAS in preterm infants and a lack of a validated scoring system specifically designed for this population [9]. It is important to consider maternal substance use when interpreting abdominal films and clinical signs of a surgical abdomen. These findings may help reduce the need for exploratory laparotomy in neonates presenting with a query of a surgical abdomen, if maternal substance use history is known.
Interestingly, there was a case report of an infant in Italy who experienced similar paralytic ileus after treatment with fentanyl for procedural sedation while ventilated [10]. Although the exposure was of a different nature, it is important nevertheless to know that any opioid derivative has the capacity to induce ileus in the neonate, whether prenatal or postnatal. Furthermore, another preterm infant whose mother was taking clonazepam, a benzodiazepine for epilepsy, was also born with concern of a paralytic ileus [10]. This adds further support to the argument that neurologically depressing agents use by a mother during pregnancy, such as opioids and benzodiazepines, must be considered when observing an infant with radiological and clinical signs of an obstructive pathology before advancing that neonate for laparotomy.
In conclusion, the given neonate was born premature after significant in utero exposure to methadone and was thought to have a malrotation on imaging. After ruling out a surgical cause of obstruction, the only factor that could be associated with such significant ileus was determined to be maternal methadone consumption. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after 72 h, we suspect this baby had paralytic ileus secondary to maternal methadone treatment. This has never been reported in the literature and is a unique finding. Hence, this correlation is a reminder to neonatology decision makers that maternal substance use may be a significant considering factor when sending a patient with small bowel obstruction to the operating theater. Given the lack of current reports, further surveillance for this phenomenon should be conducted.
CONFLICT OF INTEREST
None declared.
FUNDING
No sources of funding were used.
ETHICS APPROVAL
Ethics approval for said case report was waived. Parental consent was gained prior to creating this manuscript.
CONSENT
All images and information presented about the given minor were used with informed consent from the individual’s legal guardian. All images were anonymized.
GUARANTOR
Veronica Mugarab Samedi is a guarantor for this publication.
ACKNOWLEDGEMENTS
Not applicable. | Transplacental | DrugAdministrationRoute | CC BY | 33732483 | 19,903,447 | 2021-03 |
What was the administration route of drug 'METHADONE HYDROCHLORIDE'? | Paralytic ileus in the neonate as a rare complication of maternal methadone treatment-a case report.
Narcotic bowel syndrome is defined as worsening abdominal bloating and cramping with chronic opiate use, leading to paralytic ileus. This syndrome is common yet underreported in adults. However, there is no current evidence of such conditions in the newborn after exposure in utero to high doses of opiates. Our patient was a female indigenous preterm infant born to a mother on a high dose of methadone. On admission at the age of 12 h, she was found to have significant gastric distension. Initial abdominal X-ray showed a large gastric bubble with little evidence of rectal gas. Malrotation was suspected and surgical intervention was discussed. However, repeat abdominal X-ray, ultrasound and upper Gastrointestinal series were found to be normal and without acute findings. Thus, surgery was avoided. The gastric distension resolved spontaneously. She never required opiate therapy for neonatal abstinence syndrome. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after removal of maternal methadone, we suspect this baby had neonatal narcotic bowel syndrome. This has never been reported in the literature and is a unique finding. Given the lack of current reports, further observations for this syndrome should be conducted.
INTRODUCTION
Opioids are potent analgesic agents used to treat severe pain that is both acute and chronic in nature [1]. Common side effects include constipation and bowel dysfunction [1]. This is a result of action of opioids on receptors that line the gastrointestinal tract [1]. Chronic opiate use could lead to the bowel dysfunction, constipations or paralytic ileus [2]. In the pregnant population, illicit opioid use is found in approximately 0.1% of all pregnancies [3]. Currently, the recommended pharmacotherapy for opioid dependency in the antenatal period is methadone, which was found to diminish illicit use [3–5]. The most common side effect of maternal methadone and opiate use is neonatal abstinence syndrome (NAS), a set of signs and symptoms related to nervous system dysfunction that increases morbidity and prolongs NICU stay [3, 5]. In the available literature, we did not find reports describing early-onset gastrointestinal dysfunction in the neonates exposed to opiates and methadone in utero. In the given case report, we present a neonate with physical signs and radiologic evidence of ileus secondary to maternal methadone ingestion.
CASE REPORT
This baby girl was born via home spontaneous vaginal delivery at approximately 32 weeks to a mother with no prenatal care or ultrasounds. She was HIV negative, and the remainder of serology results and GBS status were unknown. Subsequent postnatal screening was negative. The mother had a remote history of illicit drug use and was on maintenance therapy with methadone 100 mg/day throughout pregnancy. She was taking it as prescribed, which was confirmed by home visits. She had no other illicit substance use. She did intermittently smoke cigarettes and marijuana during the first trimester of pregnancy. She did not specify any alcohol use. Baby was born at home by spontaneous precipitous delivery and brought to a peripheral hospital by ambulance for further care. Her birth weight was 1392 g. Secondary to worsening respiratory distress, she was intubated and transferred to our tertiary care center.
On admission, she was screened for infection and started on empiric antibiotics. Blood cultures were negative. Baby was clinically stable but was found to have abdominal distension and was nil per os. The initial abdominal X-ray (Fig. 1a) showed massive gastric distension with minimal gas pattern in the rest of the gut. There was no concern of duodenal atresia given the gas pattern; however, gastric outlet obstruction or malrotation could not be ruled out. Intermittent NG suctioning was then applied for gastric decompression and only air was aspirated. No vomiting or bilious aspirates were noted. An abdominal X-ray was repeated an hour later, showing the stomach had been deflated with air again being present in the distal transverse, descending and rectosigmoid colon (Fig. 1b). A further X-ray was done 2 h later showing reaccumulation of air in the stomach and bowel loops distended throughout the left abdomen (Fig. 1c).
Figure 1 (a–c) Progression of the abdominal X-ray from an appearance of gastric outlet obstruction (a) to fairly decompressed (b) to a complete pattern of distension throughout the stomach, small and large bowels (c).
Therefore, an abdominal ultrasound was conducted to rule out malrotation and assess the gut vasculature. The superior mesenteric artery and vein were found to be in normal orientation. Furthermore, pediatric surgery was promptly consulted after the ultrasound and saw no acute need for exploratory laparotomy. They recommended an upper Gastrointestinal (GI) series after 2 days of gastric decompression. In the meantime, the patient was hemodynamically stable. The upper GI series showed no acute obstruction or other significant findings (Fig. 2a–d). The abdominal distension resolved within 72 h of life at which time she passed meconium. Feeds were started with preterm formula at the same time and were tolerated well. No further abdominal foci was identified. She was successfully extubated on Day 7 of life and off respiratory support by Day 9 of life. Screening head ultrasounds and chest X-rays were normal. The infant had no clinical signs of NAS. Feeds were progressed over the subsequent 3 weeks on standard formula prior to discharge after a total of 6 weeks in NICU.
Figure 2 (a–c) Normal upper GI series; (d, e) normal upper GI series and final X-ray showing normal distribution of contrast throughout the small and large bowel.
DISCUSSION
For more than 30 years, methadone has been used as a first-line medication for opioid substitution therapy during pregnancy [5]. Despite the strong evidence supporting the use of methadone in pregnancy, methadone use is not without risk or side effects [5, 6]. Methadone does not only cross the placental barrier but is also retained by the placenta in a substantial amount [4]. There is not enough data describing fetal opioid elimination, however, placental inactivation of methadone is significantly lower than that of the maternal liver [6–8]. The elimination half-life of methadone in an opioid-tolerant patient is approximately 24 h; and in neonates, it could be as high as 40–55 h [6, 7]. The extended elimination half-life in neonates contributes to higher mg per kg-based dose [6].
There is well-documented evidence of delay of feeding onset and attaining full feeds in neonates with NAS or exposed to morphine in the NICU for analgesia [9, 10]. Fortunately, these effects are transient with no acquired GI complications [7, 8]. Our patient was off respiratory support in 9 days. Her infectious status was negative. However, abdominal distension persisted for 72 h. Her mother did not use other substances late in pregnancy other than methadone. Given that the neonate reported in this case study did not show signs of NAS, it seems less likely that we can contribute her clinical picture of ileus to her methadone exposure. However, the preterm neonates have lower rates of NAS compared to term babies [8], so she may not have displayed symptoms of withdrawal due to her prematurity. This association may well be due to the challenges of assessment of NAS in preterm infants and a lack of a validated scoring system specifically designed for this population [9]. It is important to consider maternal substance use when interpreting abdominal films and clinical signs of a surgical abdomen. These findings may help reduce the need for exploratory laparotomy in neonates presenting with a query of a surgical abdomen, if maternal substance use history is known.
Interestingly, there was a case report of an infant in Italy who experienced similar paralytic ileus after treatment with fentanyl for procedural sedation while ventilated [10]. Although the exposure was of a different nature, it is important nevertheless to know that any opioid derivative has the capacity to induce ileus in the neonate, whether prenatal or postnatal. Furthermore, another preterm infant whose mother was taking clonazepam, a benzodiazepine for epilepsy, was also born with concern of a paralytic ileus [10]. This adds further support to the argument that neurologically depressing agents use by a mother during pregnancy, such as opioids and benzodiazepines, must be considered when observing an infant with radiological and clinical signs of an obstructive pathology before advancing that neonate for laparotomy.
In conclusion, the given neonate was born premature after significant in utero exposure to methadone and was thought to have a malrotation on imaging. After ruling out a surgical cause of obstruction, the only factor that could be associated with such significant ileus was determined to be maternal methadone consumption. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after 72 h, we suspect this baby had paralytic ileus secondary to maternal methadone treatment. This has never been reported in the literature and is a unique finding. Hence, this correlation is a reminder to neonatology decision makers that maternal substance use may be a significant considering factor when sending a patient with small bowel obstruction to the operating theater. Given the lack of current reports, further surveillance for this phenomenon should be conducted.
CONFLICT OF INTEREST
None declared.
FUNDING
No sources of funding were used.
ETHICS APPROVAL
Ethics approval for said case report was waived. Parental consent was gained prior to creating this manuscript.
CONSENT
All images and information presented about the given minor were used with informed consent from the individual’s legal guardian. All images were anonymized.
GUARANTOR
Veronica Mugarab Samedi is a guarantor for this publication.
ACKNOWLEDGEMENTS
Not applicable. | Transplacental | DrugAdministrationRoute | CC BY | 33732483 | 19,903,447 | 2021-03 |
What was the outcome of reaction 'Narcotic bowel syndrome'? | Paralytic ileus in the neonate as a rare complication of maternal methadone treatment-a case report.
Narcotic bowel syndrome is defined as worsening abdominal bloating and cramping with chronic opiate use, leading to paralytic ileus. This syndrome is common yet underreported in adults. However, there is no current evidence of such conditions in the newborn after exposure in utero to high doses of opiates. Our patient was a female indigenous preterm infant born to a mother on a high dose of methadone. On admission at the age of 12 h, she was found to have significant gastric distension. Initial abdominal X-ray showed a large gastric bubble with little evidence of rectal gas. Malrotation was suspected and surgical intervention was discussed. However, repeat abdominal X-ray, ultrasound and upper Gastrointestinal series were found to be normal and without acute findings. Thus, surgery was avoided. The gastric distension resolved spontaneously. She never required opiate therapy for neonatal abstinence syndrome. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after removal of maternal methadone, we suspect this baby had neonatal narcotic bowel syndrome. This has never been reported in the literature and is a unique finding. Given the lack of current reports, further observations for this syndrome should be conducted.
INTRODUCTION
Opioids are potent analgesic agents used to treat severe pain that is both acute and chronic in nature [1]. Common side effects include constipation and bowel dysfunction [1]. This is a result of action of opioids on receptors that line the gastrointestinal tract [1]. Chronic opiate use could lead to the bowel dysfunction, constipations or paralytic ileus [2]. In the pregnant population, illicit opioid use is found in approximately 0.1% of all pregnancies [3]. Currently, the recommended pharmacotherapy for opioid dependency in the antenatal period is methadone, which was found to diminish illicit use [3–5]. The most common side effect of maternal methadone and opiate use is neonatal abstinence syndrome (NAS), a set of signs and symptoms related to nervous system dysfunction that increases morbidity and prolongs NICU stay [3, 5]. In the available literature, we did not find reports describing early-onset gastrointestinal dysfunction in the neonates exposed to opiates and methadone in utero. In the given case report, we present a neonate with physical signs and radiologic evidence of ileus secondary to maternal methadone ingestion.
CASE REPORT
This baby girl was born via home spontaneous vaginal delivery at approximately 32 weeks to a mother with no prenatal care or ultrasounds. She was HIV negative, and the remainder of serology results and GBS status were unknown. Subsequent postnatal screening was negative. The mother had a remote history of illicit drug use and was on maintenance therapy with methadone 100 mg/day throughout pregnancy. She was taking it as prescribed, which was confirmed by home visits. She had no other illicit substance use. She did intermittently smoke cigarettes and marijuana during the first trimester of pregnancy. She did not specify any alcohol use. Baby was born at home by spontaneous precipitous delivery and brought to a peripheral hospital by ambulance for further care. Her birth weight was 1392 g. Secondary to worsening respiratory distress, she was intubated and transferred to our tertiary care center.
On admission, she was screened for infection and started on empiric antibiotics. Blood cultures were negative. Baby was clinically stable but was found to have abdominal distension and was nil per os. The initial abdominal X-ray (Fig. 1a) showed massive gastric distension with minimal gas pattern in the rest of the gut. There was no concern of duodenal atresia given the gas pattern; however, gastric outlet obstruction or malrotation could not be ruled out. Intermittent NG suctioning was then applied for gastric decompression and only air was aspirated. No vomiting or bilious aspirates were noted. An abdominal X-ray was repeated an hour later, showing the stomach had been deflated with air again being present in the distal transverse, descending and rectosigmoid colon (Fig. 1b). A further X-ray was done 2 h later showing reaccumulation of air in the stomach and bowel loops distended throughout the left abdomen (Fig. 1c).
Figure 1 (a–c) Progression of the abdominal X-ray from an appearance of gastric outlet obstruction (a) to fairly decompressed (b) to a complete pattern of distension throughout the stomach, small and large bowels (c).
Therefore, an abdominal ultrasound was conducted to rule out malrotation and assess the gut vasculature. The superior mesenteric artery and vein were found to be in normal orientation. Furthermore, pediatric surgery was promptly consulted after the ultrasound and saw no acute need for exploratory laparotomy. They recommended an upper Gastrointestinal (GI) series after 2 days of gastric decompression. In the meantime, the patient was hemodynamically stable. The upper GI series showed no acute obstruction or other significant findings (Fig. 2a–d). The abdominal distension resolved within 72 h of life at which time she passed meconium. Feeds were started with preterm formula at the same time and were tolerated well. No further abdominal foci was identified. She was successfully extubated on Day 7 of life and off respiratory support by Day 9 of life. Screening head ultrasounds and chest X-rays were normal. The infant had no clinical signs of NAS. Feeds were progressed over the subsequent 3 weeks on standard formula prior to discharge after a total of 6 weeks in NICU.
Figure 2 (a–c) Normal upper GI series; (d, e) normal upper GI series and final X-ray showing normal distribution of contrast throughout the small and large bowel.
DISCUSSION
For more than 30 years, methadone has been used as a first-line medication for opioid substitution therapy during pregnancy [5]. Despite the strong evidence supporting the use of methadone in pregnancy, methadone use is not without risk or side effects [5, 6]. Methadone does not only cross the placental barrier but is also retained by the placenta in a substantial amount [4]. There is not enough data describing fetal opioid elimination, however, placental inactivation of methadone is significantly lower than that of the maternal liver [6–8]. The elimination half-life of methadone in an opioid-tolerant patient is approximately 24 h; and in neonates, it could be as high as 40–55 h [6, 7]. The extended elimination half-life in neonates contributes to higher mg per kg-based dose [6].
There is well-documented evidence of delay of feeding onset and attaining full feeds in neonates with NAS or exposed to morphine in the NICU for analgesia [9, 10]. Fortunately, these effects are transient with no acquired GI complications [7, 8]. Our patient was off respiratory support in 9 days. Her infectious status was negative. However, abdominal distension persisted for 72 h. Her mother did not use other substances late in pregnancy other than methadone. Given that the neonate reported in this case study did not show signs of NAS, it seems less likely that we can contribute her clinical picture of ileus to her methadone exposure. However, the preterm neonates have lower rates of NAS compared to term babies [8], so she may not have displayed symptoms of withdrawal due to her prematurity. This association may well be due to the challenges of assessment of NAS in preterm infants and a lack of a validated scoring system specifically designed for this population [9]. It is important to consider maternal substance use when interpreting abdominal films and clinical signs of a surgical abdomen. These findings may help reduce the need for exploratory laparotomy in neonates presenting with a query of a surgical abdomen, if maternal substance use history is known.
Interestingly, there was a case report of an infant in Italy who experienced similar paralytic ileus after treatment with fentanyl for procedural sedation while ventilated [10]. Although the exposure was of a different nature, it is important nevertheless to know that any opioid derivative has the capacity to induce ileus in the neonate, whether prenatal or postnatal. Furthermore, another preterm infant whose mother was taking clonazepam, a benzodiazepine for epilepsy, was also born with concern of a paralytic ileus [10]. This adds further support to the argument that neurologically depressing agents use by a mother during pregnancy, such as opioids and benzodiazepines, must be considered when observing an infant with radiological and clinical signs of an obstructive pathology before advancing that neonate for laparotomy.
In conclusion, the given neonate was born premature after significant in utero exposure to methadone and was thought to have a malrotation on imaging. After ruling out a surgical cause of obstruction, the only factor that could be associated with such significant ileus was determined to be maternal methadone consumption. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after 72 h, we suspect this baby had paralytic ileus secondary to maternal methadone treatment. This has never been reported in the literature and is a unique finding. Hence, this correlation is a reminder to neonatology decision makers that maternal substance use may be a significant considering factor when sending a patient with small bowel obstruction to the operating theater. Given the lack of current reports, further surveillance for this phenomenon should be conducted.
CONFLICT OF INTEREST
None declared.
FUNDING
No sources of funding were used.
ETHICS APPROVAL
Ethics approval for said case report was waived. Parental consent was gained prior to creating this manuscript.
CONSENT
All images and information presented about the given minor were used with informed consent from the individual’s legal guardian. All images were anonymized.
GUARANTOR
Veronica Mugarab Samedi is a guarantor for this publication.
ACKNOWLEDGEMENTS
Not applicable. | Recovered | ReactionOutcome | CC BY | 33732483 | 19,374,172 | 2021-03 |
What was the outcome of reaction 'Respiratory distress'? | Paralytic ileus in the neonate as a rare complication of maternal methadone treatment-a case report.
Narcotic bowel syndrome is defined as worsening abdominal bloating and cramping with chronic opiate use, leading to paralytic ileus. This syndrome is common yet underreported in adults. However, there is no current evidence of such conditions in the newborn after exposure in utero to high doses of opiates. Our patient was a female indigenous preterm infant born to a mother on a high dose of methadone. On admission at the age of 12 h, she was found to have significant gastric distension. Initial abdominal X-ray showed a large gastric bubble with little evidence of rectal gas. Malrotation was suspected and surgical intervention was discussed. However, repeat abdominal X-ray, ultrasound and upper Gastrointestinal series were found to be normal and without acute findings. Thus, surgery was avoided. The gastric distension resolved spontaneously. She never required opiate therapy for neonatal abstinence syndrome. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after removal of maternal methadone, we suspect this baby had neonatal narcotic bowel syndrome. This has never been reported in the literature and is a unique finding. Given the lack of current reports, further observations for this syndrome should be conducted.
INTRODUCTION
Opioids are potent analgesic agents used to treat severe pain that is both acute and chronic in nature [1]. Common side effects include constipation and bowel dysfunction [1]. This is a result of action of opioids on receptors that line the gastrointestinal tract [1]. Chronic opiate use could lead to the bowel dysfunction, constipations or paralytic ileus [2]. In the pregnant population, illicit opioid use is found in approximately 0.1% of all pregnancies [3]. Currently, the recommended pharmacotherapy for opioid dependency in the antenatal period is methadone, which was found to diminish illicit use [3–5]. The most common side effect of maternal methadone and opiate use is neonatal abstinence syndrome (NAS), a set of signs and symptoms related to nervous system dysfunction that increases morbidity and prolongs NICU stay [3, 5]. In the available literature, we did not find reports describing early-onset gastrointestinal dysfunction in the neonates exposed to opiates and methadone in utero. In the given case report, we present a neonate with physical signs and radiologic evidence of ileus secondary to maternal methadone ingestion.
CASE REPORT
This baby girl was born via home spontaneous vaginal delivery at approximately 32 weeks to a mother with no prenatal care or ultrasounds. She was HIV negative, and the remainder of serology results and GBS status were unknown. Subsequent postnatal screening was negative. The mother had a remote history of illicit drug use and was on maintenance therapy with methadone 100 mg/day throughout pregnancy. She was taking it as prescribed, which was confirmed by home visits. She had no other illicit substance use. She did intermittently smoke cigarettes and marijuana during the first trimester of pregnancy. She did not specify any alcohol use. Baby was born at home by spontaneous precipitous delivery and brought to a peripheral hospital by ambulance for further care. Her birth weight was 1392 g. Secondary to worsening respiratory distress, she was intubated and transferred to our tertiary care center.
On admission, she was screened for infection and started on empiric antibiotics. Blood cultures were negative. Baby was clinically stable but was found to have abdominal distension and was nil per os. The initial abdominal X-ray (Fig. 1a) showed massive gastric distension with minimal gas pattern in the rest of the gut. There was no concern of duodenal atresia given the gas pattern; however, gastric outlet obstruction or malrotation could not be ruled out. Intermittent NG suctioning was then applied for gastric decompression and only air was aspirated. No vomiting or bilious aspirates were noted. An abdominal X-ray was repeated an hour later, showing the stomach had been deflated with air again being present in the distal transverse, descending and rectosigmoid colon (Fig. 1b). A further X-ray was done 2 h later showing reaccumulation of air in the stomach and bowel loops distended throughout the left abdomen (Fig. 1c).
Figure 1 (a–c) Progression of the abdominal X-ray from an appearance of gastric outlet obstruction (a) to fairly decompressed (b) to a complete pattern of distension throughout the stomach, small and large bowels (c).
Therefore, an abdominal ultrasound was conducted to rule out malrotation and assess the gut vasculature. The superior mesenteric artery and vein were found to be in normal orientation. Furthermore, pediatric surgery was promptly consulted after the ultrasound and saw no acute need for exploratory laparotomy. They recommended an upper Gastrointestinal (GI) series after 2 days of gastric decompression. In the meantime, the patient was hemodynamically stable. The upper GI series showed no acute obstruction or other significant findings (Fig. 2a–d). The abdominal distension resolved within 72 h of life at which time she passed meconium. Feeds were started with preterm formula at the same time and were tolerated well. No further abdominal foci was identified. She was successfully extubated on Day 7 of life and off respiratory support by Day 9 of life. Screening head ultrasounds and chest X-rays were normal. The infant had no clinical signs of NAS. Feeds were progressed over the subsequent 3 weeks on standard formula prior to discharge after a total of 6 weeks in NICU.
Figure 2 (a–c) Normal upper GI series; (d, e) normal upper GI series and final X-ray showing normal distribution of contrast throughout the small and large bowel.
DISCUSSION
For more than 30 years, methadone has been used as a first-line medication for opioid substitution therapy during pregnancy [5]. Despite the strong evidence supporting the use of methadone in pregnancy, methadone use is not without risk or side effects [5, 6]. Methadone does not only cross the placental barrier but is also retained by the placenta in a substantial amount [4]. There is not enough data describing fetal opioid elimination, however, placental inactivation of methadone is significantly lower than that of the maternal liver [6–8]. The elimination half-life of methadone in an opioid-tolerant patient is approximately 24 h; and in neonates, it could be as high as 40–55 h [6, 7]. The extended elimination half-life in neonates contributes to higher mg per kg-based dose [6].
There is well-documented evidence of delay of feeding onset and attaining full feeds in neonates with NAS or exposed to morphine in the NICU for analgesia [9, 10]. Fortunately, these effects are transient with no acquired GI complications [7, 8]. Our patient was off respiratory support in 9 days. Her infectious status was negative. However, abdominal distension persisted for 72 h. Her mother did not use other substances late in pregnancy other than methadone. Given that the neonate reported in this case study did not show signs of NAS, it seems less likely that we can contribute her clinical picture of ileus to her methadone exposure. However, the preterm neonates have lower rates of NAS compared to term babies [8], so she may not have displayed symptoms of withdrawal due to her prematurity. This association may well be due to the challenges of assessment of NAS in preterm infants and a lack of a validated scoring system specifically designed for this population [9]. It is important to consider maternal substance use when interpreting abdominal films and clinical signs of a surgical abdomen. These findings may help reduce the need for exploratory laparotomy in neonates presenting with a query of a surgical abdomen, if maternal substance use history is known.
Interestingly, there was a case report of an infant in Italy who experienced similar paralytic ileus after treatment with fentanyl for procedural sedation while ventilated [10]. Although the exposure was of a different nature, it is important nevertheless to know that any opioid derivative has the capacity to induce ileus in the neonate, whether prenatal or postnatal. Furthermore, another preterm infant whose mother was taking clonazepam, a benzodiazepine for epilepsy, was also born with concern of a paralytic ileus [10]. This adds further support to the argument that neurologically depressing agents use by a mother during pregnancy, such as opioids and benzodiazepines, must be considered when observing an infant with radiological and clinical signs of an obstructive pathology before advancing that neonate for laparotomy.
In conclusion, the given neonate was born premature after significant in utero exposure to methadone and was thought to have a malrotation on imaging. After ruling out a surgical cause of obstruction, the only factor that could be associated with such significant ileus was determined to be maternal methadone consumption. Given the pattern of gas seen on the initial abdominal X-ray and its spontaneous resolution after 72 h, we suspect this baby had paralytic ileus secondary to maternal methadone treatment. This has never been reported in the literature and is a unique finding. Hence, this correlation is a reminder to neonatology decision makers that maternal substance use may be a significant considering factor when sending a patient with small bowel obstruction to the operating theater. Given the lack of current reports, further surveillance for this phenomenon should be conducted.
CONFLICT OF INTEREST
None declared.
FUNDING
No sources of funding were used.
ETHICS APPROVAL
Ethics approval for said case report was waived. Parental consent was gained prior to creating this manuscript.
CONSENT
All images and information presented about the given minor were used with informed consent from the individual’s legal guardian. All images were anonymized.
GUARANTOR
Veronica Mugarab Samedi is a guarantor for this publication.
ACKNOWLEDGEMENTS
Not applicable. | Recovered | ReactionOutcome | CC BY | 33732483 | 19,374,172 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood lactate dehydrogenase increased'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dermatitis acneiform'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ejection fraction decreased'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'General physical health deterioration'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant melanoma'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, DOXYCYCLINE, MINOCYCLINE HYDROCHLORIDE, PREDNISOLONE, RIBOCICLIB, TETRACYCLINE | DrugsGivenReaction | CC BY | 33732653 | 20,162,185 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, DOXYCYCLINE, MINOCYCLINE HYDROCHLORIDE, PREDNISOLONE, RIBOCICLIB, TETRACYCLINE | DrugsGivenReaction | CC BY | 33732653 | 20,162,185 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonitis'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Protein S increased'. | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | BINIMETINIB, RIBOCICLIB | DrugsGivenReaction | CC BY | 33732653 | 20,877,777 | 2021 |
What was the administration route of drug 'DOXYCYCLINE'? | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY | 33732653 | 20,162,185 | 2021 |
What was the administration route of drug 'MINOCYCLINE HYDROCHLORIDE'? | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY | 33732653 | 20,162,185 | 2021 |
What was the administration route of drug 'PREDNISOLONE'? | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33732653 | 20,162,185 | 2021 |
What was the administration route of drug 'TETRACYCLINE'? | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY | 33732653 | 20,162,185 | 2021 |
What was the outcome of reaction 'Dermatitis acneiform'? | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33732653 | 20,877,777 | 2021 |
What was the outcome of reaction 'Ejection fraction decreased'? | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33732653 | 20,877,777 | 2021 |
What was the outcome of reaction 'Pneumonitis'? | Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.
There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Introduction
In addition to the activation of the mitogen-activated protein (MAP) kinase pathway, NRAS mutant melanomas often have additional disturbances in cell cycle regulation (1). In contrast to BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma. However, in a phase III trial, patients treated with binimetinib, a MAP kinase inhibitor achieved improved progression-free survival (PFS) compared to dacarbazine treated patients, but no improvement of overall survival (2). Other authors suggested combining MEK inhibitors with CDK4/6 inhibitors to obtain not only apoptosis but also G1 cell cycle arrest in order to achieve synergistic effects (3, 4). Preclinical mouse models show that the combination of MEK and CDK4/6 inhibitors may not only induce senescence but also make immunological “cold” tumors amenable to PD-1 checkpoint blockade, leading to accumulation of CD8+ T cells in the tumor (5). Schuler and colleagues conducted a phase 1b/2 study in NRAS mutant melanoma patients with combined MEK inhibition (binimetinib) and CDK4/6 inhibition (ribociclib) (6). Four patients had a partial response and seven patients had a stable disease, resulting in a disease control rate of 11/16 (69%). Of note, all patients with partial response had concurrent CDKN2A alterations. Binimetinib and ribociclib showed no detectable negative drug interactions and no additional side effects were observed besides those known from the respective monotherapies (7, 8). Here we present a patient with partial response to combined binimetinib and ribociclib therapy after molecular defects had been characterized by panel sequencing.
Methods
The patient provided written informed consent for the use of her clinical data for research purposes and for publication of this case report. The local independent Research Ethics Committee (IEC) approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The Declaration of Helsinki was respected. Detailed methodology is available in Supplementary Appendix .
Case Report
A 56 year old female melanoma patient had progressive disease after 1 year of adjuvant nivolumab therapy (480mg q28) following resection of transit and lymph node metastases. In 2011, the first diagnosis of an ulcerated nodular melanoma of the foot with a tumor thickness of 2.75mm was made, excision with 2cm safety distance and sentinel node had been tumor free. She had no comorbidities and was not taking any medication. There was no family history of melanoma.
As the patient developed liver, lymph node and soft tissue metastases, she was treated by four cycles of combined immunotherapy with ipilimumab 1mg/kg and nivolumab 3mg/kg every 3 weeks. However, within 3 months, there was a further progression with multiple liver metastases up to a diameter of 12cm. Therefore, treatment with chemosaturation was initiated, according to the recommendation of the interdisciplinary tumor board. Since the tumor was BRAF codon 600 wildtype, but NRAS mutated, nivolumab was continued as monotherapy despite progressive metastases in the pancreas and subcutaneous tissue of the abdomen. The next staging by PET/CT 2 months later revealed another extensive progression with newly detected bone and lung metastases. Only the liver metastases treated by chemosaturation remained stable.
Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the known NRAS mutation, and also amplification of CCNE1 and CDK6 (3 copies) ( Figure 1 ). The tumor mutation load was 4.94 Var/Mbp.
Figure 1 NGS analysis. General characteristics and potential relevant somatic variants were listed according to the diagnostic report. Somatic copy number variant (CNV) are shown as pictogram of the IGV view. Deletions are depicted in red, amplifications in blue. The homozygote deletion of the CDKN2A locus on the chromosome 9 is marked by the red dot.
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21, as well as high expression of CDK6 and cyclin D1. RB1 loss was excluded, but 20% of RB were phosphorylated, confirming that the tumor had a major defect in the senescence inducing pathway (9).
According to the recommendation of the molecular tumor board, a targeted therapy with combined MEK and CDK4/6 inhibition was initiated.The treatment response was monitored with PET/CT and liquid biopsy, serum LDH, and S100. Since ribociclib 200mg per day 21d q28 in combination with binimetinib 45mg twice daily was found to be the optimal regime for melanoma therapy (6), we started this combination with exactly that dose and schedule, when echocardiography showed a normal left ventricular ejection rate.
Immediately before starting combined binimetinib and ribociclib, a painful subcutaneous metastasis on the left axilla was surgically removed. This metastasis also underwent immunohistochemical validation of the cell cycle genes with comparable results ( Figures 2A–F ) and was used to prepare slice cultures.
Figure 2 Immunohistochemical panel (A–H). (A) A solid tumor composed of atypical enlarged cells with increased mitotic activity, hematoxylin and eosin staining, 200x original magnification, (B) All cells have preserved retinoblastoma 1 protein (insert), whereas about 30% of RB is phosphorylated (main picture, phospho-RB antibody). (C) The tumor cells show a loss of p16 (only stroma cells are positive) and nearly all cells are negative for p21 (D). (E) Moderate to strong positivity for cyclin D1 in the majority of the tumor cells. (F) Strong and homogenous positivity for CDK6 in all tumor cells. (G) Moderate nuclear and cytoplasmic positivity for phospho-p44/42 MAPK in a vast amount of tumor cells (primarily at the invasive front). (H) weak, primarily cytoplasmic positivity for phosphor-p38 MAPK in a minority of tumor cells (primarily in the invasive front). (B–H) Immunoperoxidase, 200x original magnification). In vitro models used for efficacy testing of binimetinib plus ribociclib (I–L). (I) Alamar blue assay of metastasis slice cultures shows reduced cell viability after combined ribociclib and binimetinib treatment: (mean +/−SD, n=4; *p < 0.05; One-way ANOVA with Sidak’s multiple comparisons test versus untreated controls). (J) Melanoma cells isolated from a patient-derived xenograft tumor generated with tumor cells of the metastasis used in subfigure I show reduced viability after combined ribociclib and binimetinib treatment (alamarBlue assay) (mean +/− SD, n=6). (K, L) Senescence-associated beta-galactosidase of isolated melanoma cells show more intensive staining with combined ribociclib and binimetinib treatment indicating senescence. Percentage of senescent cells is depicted as clear blue cell count normalized to the total cell count (mean +/− SD, n=6, *p < 0.05, **p < 0.01).
Supporting the therapy with a MEK inhibitor, the immunhistochemistry for phospho-p44/42 MAPK (ERK1/2, downstream targets of MEK) showed a moderate positivity in a vast amount of tumor cells in the invasion front. Phospho-p38 MAPK showed only a weak positivity (lower than adjacent endothelial cells) ( Figures 2G, H ).
The slice cultures were treated in vitro with either ribociclib or binimetinib alone or with the combination. The combination reduced the viability of the tumor tissue after 4 days compared to the untreated control ( Figure 2I ).
In order to amplify ribociclib and binimetinib naïve melanoma cells, a few vital tumor cells of the subcutaneous metastasis were injected in a NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This patient-derived xenograft (PDX) was used to re-isolate melanoma cells for further in vitro tests after a solid tumor had grown. These cells proved the efficacy of both drugs in combination in an alamarBlue viability assay ( Figure 2J ). Furthermore, senescence-associated beta-galactosidase staining was performed after 3 days of treatment. We observed that the maximum measurable effect was about 30% of beta-galactosidase positive cells. This was found at already low concentrations by SA-b-galactosidase staining when compared to the monotherapies ( Figures 2K, L ).
Apart from an acneiform eruption that was controlled by oral tetracycline (doxycycline 100mg or later minocycline 50mg), the patient had no side effects during the first weeks of therapy.
LDH increased slightly during the course of therapy and S100 also remained significantly elevated after an initial decline. In contrast, NRAS mutation in the liquid biopsy, initially detectable with an allele frequency of 2%, dropped significantly to 0.9 and 0.37% after 4 weeks of therapy. Six weeks after therapy start, cell-free tumor DNA was undetectable ( Figure 3 ). In line with the NRAS monitoring in liquid biopsy, PET/CT 8 weeks after initiation of therapy showed a remarkable reduction of whole-body vital tumor mass ( Figures 4A, B ).
Figure 3 Time line of patient’s history and in detail time course of lactate dehydrogenase (LDH) and S100 levels as well as NRAS c.182A>G/p.Q61R allele fractions in liquid biopsy after initiation of ribociclib and binimetinib therapy. Upper part: time line depicts patient’s disease course with different treatments. Lower part (magnification of time course during therapy with ribociclib and binimetinib): monitoring shows elevated LDH and S100 levels during the course of therapy while NRAS c.182A>G/p.Q61R allele fraction in liquid biopsy decreased and dropped below limit of detection with deviations after six weeks and twelve weeks (analysis limit of detection 0.21–0.69%, depth 2,393–75,606, mol depth 603–3,486). LDH and S100 normal value ranges are depicted as purple and green dashed lines. Horizontal arrows indicate periods of kinase inhibitor treatment. Vertical arrows indicate time points of follow-up PET/CT and thorax CT staging.
Figure 4 18F-FDG PET/CT baseline and 8 weeks of treatment with ribociclib and binimetinib (A, B). (A) 18F-FDG PET/CT at baseline staging showing 18F-FDG avid metastases in soft tissue (upper row), sacral bone (middle row), liver, and pancreas (lower row). (B) At follow-up staging after 8 weeks of treatment with ribociclib und binimetinib, soft tissue metastases decreased in size and had a significantly reduced 18F-FDG uptake (upper row). The sacral bone metastasis showed an almost complete reduction of 18F-FDG accumulation (middle row). Pancreas and liver metastases transformed necrotic with lower amount of solid tumor masses and significantly reduced 18F-FDG uptake (lower row). A 18F-FDG avid metastasis was still observed in the pancreatic head. The whole-body tumor volumetric parameters, defined as the sum of all 18F-FDG avid metastases, were considerably decreased at follow-up (whole-body MTV: 20.6 cm3; whole-body TLG: 156.2) compared to baseline staging (whole-body MTV: 66.0 cm3; whole-body TLG: 582.3). Rapid recovery of pneumonitis after 12 days (C, D). (C) Partly flat milky glass-like, partly spotty consolidating infiltrates typical findings for pneumonitis. (D) Complete recovery 12 days later with 100mg prednisolone.
However, 15 weeks after treatment initiation, the patient developed a marked deterioration in her general condition and dyspnea during minimal physical activity.
Thoracic CT revealed severe pneumonitis, probably binimetinib-induced ( Figures 4C, D ). In addition echocardiography showed a significant reduction of the left ventricular ejection fraction to 24%, most probably also caused by the current therapy. The patient was hospitalized and treated with high-dose corticosteroids: 100mg prednisolone intravenously per day. Therapy with binimetinib and ribociclib was interrupted. Furthermore, diuretics and beta-blocker were started. Just 1 day after the first steroid administration the patient felt much better and was able to climb stairs again after a few more days. Prednisolone was reduced by 20mg per week and 12 days after diagnosis, pneumonitis had completely resolved ( Figure 4D ). By this time, left ventricular ejection fraction had improved to 37%. Treatment with ribociclib was re-started in a dosage of 400mg per day 21d q28. Binimetinib was reintroduced 4 weeks later, when the echocardiography showed a normal left venticular ejection fraction of 59%. At this time, PET/CT results revealed progression on ribociclib monotherapy. We therefore re-started MEK inhibition with trametinib 0.5mg per day, one quarter of the recommended daily dose. One week later, when there were still no clinical signs of pneumonitis or cardiotoxicity, trametinib was increased to 0.75mg per day. During treatment interruption the mutant alleles of NRAS c.182A>G/p.Q61R had increased again to 0.59% in the cfDNA, decreasing after re-initiation of ribociclib to 0.33% and furthermore to 0.19% after supplementing trametinib ( Figure 3 ).
As 14 days after the initiation of trametinib, echocardiography showed still normal left ventricular ejection fraction and the patient had no clinical signs of pneumonitis, we increased trametinib to 1mg per day under close clinical supervision. Echocardiography and thoracic CT follow-up remained stable under the treatment regime with ribociclib 400mg 21d q28 and trametinib 1mg per day without prednisolone therapy.
Discussion
This case report demonstrates how an individual, molecular-based therapeutic approach could be found based on next-generation sequencing results. Of advantage was the already established treatment regime and dosis for the combination of binimetinib and ribociclib from a phase 1b/2 trial (6). With molecular-based off-label therapy, it is important to evaluate potential treatment success or failure of as early and as reliably as possible. We therefore performed PET/CT immediately before the start of therapy and also collected liquid biopsies in addition to the established tests such as S100 and LDH. Since fresh tissue could be obtained before starting the therapy, it was also possible to establish a PDX model to test the efficacy of the two drugs ex vivo. Due to the urgency with the rapid tumor growth, we performed the testing in parallel to therapy initiation. However, PDX models have their greatest importance at an earlier point in time, before the actual start of the therapy. Furthermore, the PDX model could not be used as a therapy in vivo model due to regulatory requirements. Together with further in-depth experiments, a deeper understanding of the interaction of binimetinib and ribociclib should be generated, which our case study cannot provide. In our patient, monotherapy with either binimetinib or ribociclib alone was less effective than the combination. This fits well with the published results: CDK4/6 inhibitors alone suppress proliferation with little effect on apoptosis, while the drug combination of MEK and CDK4/6 inhibitors induced both, apoptosis and cell cycle arrest, what should result in tumour regression (3, 4).
PET/CT is an appropriate imaging modality to assess response of such molecular-based therapeutic approaches, as it provides both, morphologic and metabolic informations of metastases (10, 11) and liquid biopsies allow specific monitoring of driver mutations during melanoma therapy (12).
The severe treatment-related adverse events of our patient, both pneumonitis and reduction of the left ventricular ejection fraction, were most likely caused by the MEK inhibitor. In the NEMO study, pneumonitis occurred in 1% of the patients treated by binimetinib and a decrease of the left ejection fraction in 4% of the patients (2). In contrast, neither a decrease in left ventricular ejection fraction nor pneumonitis was observed with CDK4/6 inhibitors (13, 14). Therefore we decided to re-start CDK4/6 inhibition earlier than MEK inhibiton. Ribociclib was re-started as soon as the pneumonitis had disappeared but as monotherapy because cardiac function had not yet fully restored. During treatment with trametinib, which was slowly increased to 50% of the recommended daily dose, there was no recurrence of cardiotoxicity or pneumonitis. This suggests that switching the drug may sometimes be helpful in managing the side effects. The progressive disease with initial ribociclib monotherapy indicates the need for combined CDK4/6 and MEK inhibition. Since further resistance mechanisms are likely to occur, we do not know how long the patient will benefit from this regimen.
This case demonstrates the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists and nuclear physicians. An interdisciplinary molecular tumor board is important for decision making of molecular-based off-label therapies. Registers should be established to collect decisions and outcomes of such molecular-based therapeutic strategies to facilitate the development of new treatment approaches. In addition, basket studies would be desirable to cover the costs of the therapies and to standardize monitoring. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Data Availability Statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .
Ethics Statement
Local Research Ethics Committee (IEC) Tuebingen approved the publication of patient data in the form of the case report. IEC-Project Number: 822/2020BO2. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author Contributions
Drafting of the manuscript: AF, TS, and IB. Molecular and pathological analysis, tumor sequencing, liquid biopsy: CS, CR, SA-E, OR, SM, DN, and IB. In vitro models: TS and HN. Radiological imaging: CPR and SG. Coordination of clinical care: AF, GM, MB, TE, CG, and MR. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2021.643156/full#supplementary-material
Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33732653 | 20,877,777 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure acute'. | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | BUSULFAN, CYCLOPHOSPHAMIDE, CYTARABINE, ETOPOSIDE, IDARUBICIN, LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN, MERCAPTOPURINE, METHOTREXATE, MITOXANTRONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33732669 | 19,095,975 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | BUSULFAN, CYCLOPHOSPHAMIDE, CYTARABINE, ETOPOSIDE, IDARUBICIN, LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN, MERCAPTOPURINE, METHOTREXATE, MITOXANTRONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33732669 | 19,095,975 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxic cardiomyopathy'. | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | BUSULFAN, CYCLOPHOSPHAMIDE, CYTARABINE, ETOPOSIDE, IDARUBICIN, LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN, MERCAPTOPURINE, METHOTREXATE, MITOXANTRONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33732669 | 19,095,975 | 2021 |
What was the dosage of drug 'BUSULFAN'? | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 3.2 MG/KG | DrugDosageText | CC BY | 33732669 | 19,095,975 | 2021 |
What was the dosage of drug 'IDARUBICIN'? | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | UNK (CUMULATIVE DOSE OF 189 MG/M2) | DrugDosageText | CC BY | 33732669 | 19,095,975 | 2021 |
What was the dosage of drug 'LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN'? | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 6 MG/KG | DrugDosageText | CC BY | 33732669 | 19,095,975 | 2021 |
What was the dosage of drug 'MITOXANTRONE HYDROCHLORIDE'? | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | 162 MG/M2 | DrugDosageText | CC BY | 33732669 | 19,095,975 | 2021 |
What was the outcome of reaction 'Cardiac failure acute'? | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33732669 | 19,095,975 | 2021 |
What was the outcome of reaction 'Toxic cardiomyopathy'? | Case Report: Low Dose of Valsartan/Sacubitril Leads to Successful Reversal of Acute Heart Failure in Chemotherapy-Induced Cardiomyopathy.
Valsartan/sacubitril is a new agent approved for the treatment of chronic heart failure in adults, with a combination of angiotensin receptor inhibitor and neprilysin inhibitor. However, the benefit of valsartan/sacubitril in pediatric patients is unknown. We herein report its clinical benefit in a case of acute decompensated heart failure in chemotherapy-induced cardiomyopathy. This case suggests that in children with acute heart failure refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Introduction
The importance of pediatric heart failure (PHF) has been emerging in clinical practice, with an incidence of 0.97–7.4 per 100,000 (1). Despite being a relatively uncommon condition, PHF is still an important cause of mortality and morbidity in the pediatric population. To date, there have been well-established guidelines for adult heart failure (HF) management. Indeed, since 2016, a novel agent with combination of angiotensin receptor and neprilysin inhibitor (ARNI), valsartan/sacubitril, had been introduced into both the European Society of Cardiology (ESC) and American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the management of adult HF (2, 3). However, the role and safety of this novel medication in children is not yet well-elucidated. Here we present a pediatric case of chemotherapy-induced dilated cardiomyopathy (DCM) with chronic HF with subsequent acute cardiac decompensation, which was successfully reversed by low dose of ARNI.
Case Description
Acute decompensated HF was presented in a 7-year-old girl. Tracing back her past history, she had acute myeloid leukemia (AML) diagnosed at the age of 1 year, receiving chemotherapy according to Taiwan Pediatric Oncology Group-Acute Myeloid Leukemia (TPOG-AML) 2008 protocol, consisting of idarubicin, cytarabine, mitoxantrone, cyclophosphamide, etoposide, methotrexate, and mercaptopurine. However, due to AML relapse, part of the TPOG-AML 2008 protocol was repeated, with cumulative dose of 189 mg/m2 for idarubicin and 162 mg/m2 for mitoxantrone.
Cyclophosphamide dose was 200 mg/m2/day for 3–5 days within a course, with total used dose of 4 g/m2. For still poor-controlled disease, she then received peripheral blood stem cell transplantation (PBSCT) when she was 5 years old. The conditioning regimen prior to transplantation included busulfan (3.2 mg/kg), anti-thymocyte globulin (6 mg/kg), and high-dose cyclophosphamide (120 mg/kg). The heart function before transplantation was normal with left ventricular ejection fraction (LVEF) 58%, no cardiomegaly in chest radiography, with a serum level of B-type natriuretic peptide (BNP) of 78 pg/ml (normal <100). However, acute HF and DCM with reduced LVEF of 35% occurred 2 weeks after PBSCT, potentially induced by anthracyclines and cyclophosphamide. Her DCM was well-controlled by captopril (1 mg/kg/day) with stable LVEF of 50% and with Modified Ross/New York Heart Association (NYHA) functional class I for about 2 years.
However, 2 years after the PBSCT, acute HF developed with manifestations of pitting edema in the lower legs and shortness of breath at rest, compatible with Modified Ross/NYHA functional class IV. The echocardiogram during admission showed reduced LVEF of 22%. Despite fluid restriction and anti-congestive agents including furosemide, ramipril, bisoprolol, and spironolactone for 2 weeks, her clinical condition slightly improved to modified Ross/NYHA III and was discharged. However, the cardiac magnetic resonance imaging (MRI) demonstrated low LVEF of 18.3%, and cardiac catheterization showed cardiac index of 1.96 L/min/m2. Therefore, she was listed in the waiting list for heart transplantation and was followed regularly in our clinic.
Unfortunately, she was admitted again to our pediatric intensive care unit (PICU) 6 months later with another episode of acute cardiac decompensation, with Modified Ross/NYHA IV. The echocardiogram showed low LVEF of 19.5%. Despite meticulous management for 2 weeks, with fluid restriction, intravenous furosemide 2 mg/kg/day, oral spironolactone 2.25 mg/kg/day, ramipril 2.5 mg/m2/day, bisoprolol 1.25 mg/day, followed by intravenous infusion of inotropic agents with dopamine and milrinone, her HF progressed with cardiomegaly, and pleural effusion even further developed (Figures 1A,B). In the context of poor response to conventional medications, we changed ramipril to the ARNI (valsartan/sacubitril). We started with the dosage of 0.8 mg/kg/dose twice daily, without further adjustment because hypotension developed while increasing the dose. Fortunately, after the initiation of valsartan/sacubitril, her urine output doubled within 2 days, BNP rapidly declined within 5 days, and pleural effusion subsided after 10 days. Under unchanged dosage of valsartan/sacubitril, accompanied with furosemide, spironolactone, and bisoprolol, she was discharged out of PICU 14 days later and discharged 17 days later. The cardiothoracic ratio on chest X-ray decreased (Figure 1C), and LVEF improved (19.5% to 35.4%) 5 weeks later. Her LVEF shown by echocardiogram increased to 56.5% 1 year later (Figure 2), and her clinical status also significantly improved to Modified Ross/NYHA I. No further adverse effects such as hypotension, electrolyte imbalance, or impaired renal function were noted.
Figure 1 Remarkable improvement in chest X-ray was noted after the initiation of valsartan/sacubitril. (A) Chest X-ray upon admission on the second episode of acute decompensation. The cardiothoracic ratio (CTR) was 0.67. (B) Chest X-ray 2 weeks after aggressive treatment with conventional anti-congestive medications and fluid restriction. Cardiomegaly persisted with progressive right pleural effusion. (C) Chest X-ray 5 weeks after valsartan/sacubitril treatment. The CTR reduced to 0.53, and the pleural effusion had been resolved.
Figure 2 The serial changes of BNP and LVEF with medications adjustment in our patient. The baseline LVEF and BNP level before PBSCT when she was 5 years old were both normal. Acute HF occurred 2 weeks after PBSCT, and long-term ACEIs including captopril and ramipril were prescribed. Two episodes of acute decompensation later developed when she was 7 years old, while the BNP and LVEF both worsened. However, significant improvement occurred after the initiation of valsartan/sacubitril and persisted even at 1-year follow-up. BNP, B-type natriuretic peptide; LVEF, left ventricular ejection fraction; PBSCT, peripheral blood stem cell transplantation; HF, heart failure; ACEIs, angiotensin-converting-enzyme inhibitors.
Discussion
Pediatric heart failure is a complex clinical syndrome resulting from mostly congenital heart disease (CHD) and cardiomyopathies (CMs). In contrast, adult HF results from ischemic heart disease in most cases. Large randomized prospective trials on PHF are lacking, and so far no strong and evidence-based recommendations within well-established guidelines for the management of PHF had been proposed. On the other hand, the mechanism and pathogenesis of chemotherapy-related cardiomyopathies, like in our case, remain controversial and poorly understood. However, the treatment of HF in these CMs patients was similar to the general HF group.
In adults, valsartan/sacubitril is the first-in-class ARNI to treat chronic HF with reduced ejection fraction (HFrEF), but its benefit is so far not yet well-elucidated in pediatric populations (4). Our case suggests that in children with acute HF refractory to conventional medications, low dose of sacubitril/valsartan may be an effective therapy.
Valsartan/sacubitril is designed based on two mechanisms: (1) the blockade of renin-angiotensin-aldosterone system (RAAS) by valsartan to prevent the harmful profibrotic effect on cardiomyocyte and (2) the inhibition of neprilysin by sacubitril, an enzyme responsible for the breakdown of natriuretic peptides, with the combined effects of vasodilation, natriuresis, diuresis, and therefore reduction in both the pre-load and afterload (5–7). According to the 2017 ACC/AHA/HFSA guideline, valsartan/sacubitril has been listed as Class I B recommendation for adult patients with chronic HFrEF and as a replacement for angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blocker (ARB) for chronic symptomatic HFrEF (3). Similar suggestions were proclaimed in the 2016 ESC guideline (2). However, in pediatric populations its safety and equivalent benefits have not yet been completely understood.
Currently, there is an ongoing pediatric multicenter trial—PANORAMA-HF study (NCT00382525)—which will compare valsartan/sacubitril and enalapril in the treatment of pediatric HFrEF (8). Fortunately, positive mid-term results had prompted the recent approval from the American Food and Drug Association (FDA) in symptomatic pediatric HFrEF patients aged 1 year and older (9).
In our case, there were two inspiring implications regarding the use of valsartan/sacubitril in pediatric patients. First, even though FDA suggested initial dose in pediatric patients of 1.6 mg/kg twice daily, the prescribed dosage in our patient was only 0.8 mg/kg twice daily to avoid hypotension throughout the 1-year follow-up but still resulted in a remarkable improvement in her cardiac function. This may imply that a lower dose is effective enough to treat PHF with the benefit of less adverse effects, especially hypotension. In line with our observation in this case, similar results of improving cardiac function in relatively low doses of valsartan/sacubitril were shown in recent adult studies (10, 11). Second, the use of valsartan/sacubitril was generally recommended in adult patients with chronic HF NYHA II-III. In our case, we found that the acute decompensation status with NYHA IV could also be stabilized after the initiation of valsartan/sacubitril. These findings suggest that there can be some differences in the dose and indications between children and adults in this agent. Further studies are needed to substantiate our findings.
To date, there are still few case reports describing the use of valsartan/sacubitril in PHF. This case report suggests that it can be effective even in lower dose and acute decompensation status in children with HF. Further ongoing clinical trials of this novel medication may be needed to investigate the optimal dose and indications in pediatric populations.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics Statement
Informed consent was obtained from the parents for publication of this case report.
Author Contributions
J-HH carried out the studies. Y-CL, Z-KD, and I-CC participated in collecting data. S-HL drafted the manuscript. Y-HW helped to draft the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | Recovered | ReactionOutcome | CC BY | 33732669 | 19,095,975 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
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. | CISPLATIN, FUROSEMIDE, MANNITOL | DrugsGivenReaction | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy toxic'. | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
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. | CISPLATIN, FUROSEMIDE, MANNITOL | DrugsGivenReaction | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
What was the administration route of drug 'CISPLATIN'? | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
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. | Intraperitoneal | DrugAdministrationRoute | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
What was the administration route of drug 'FUROSEMIDE'? | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
What was the administration route of drug 'MANNITOL'? | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
What was the dosage of drug 'CISPLATIN'? | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
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. | INFUSION; HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY | DrugDosageText | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
What was the dosage of drug 'FUROSEMIDE'? | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
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. | APPROXIMATELY 60 MIN PRIOR TO INFUSION OF CISPLATIN | DrugDosageText | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
What was the dosage of drug 'MANNITOL'? | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
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. | APPROXIMATELY 60 MIN PRIOR TO INFUSION OF CISPLATIN INTRAPERITONEALLY, THE PATIENT RECEIVED 30 G ... | DrugDosageText | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
What was the outcome of reaction 'Acute kidney injury'? | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
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. | Recovering | ReactionOutcome | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
What was the outcome of reaction 'Nephropathy toxic'? | Sodium thiosulfate for postoperative cisplatin induced nephrotoxicity following hyperthermic intraperitoneal chemotherapy: A case report.
•Cisplatin induced nephrotoxicity can occur days after administration.•Hyperthermic intraperitoneal chemotherapy with cisplatin for ovarian cancer is increasing in utilization.•Sodium thiosulfate can be used following cisplatin induced nephrotoxicity for treatment.
1 Introduction
The highly cytotoxic effect of cisplatin has led to its widespread utility as an anti-neoplastic agent for ovarian and many other types of cancers. Use of cisplatin is limited by well characterized side effects including neurotoxicity, myelosuppression, peripheral neuropathy and nephrotoxicity. For advanced ovarian cancer, cisplatin may be administered using hyperthermic intraperitoneal chemotherapy (HIPEC). This administration route allows direct and local delivery of chemotherapy to malignant cells with reduced systemic absorption (Armstrong et al., 2006, Van Driel et al., 2018). However, patients receiving intraperitoneal cisplatin still experience systemic side effects. Cisplatin is primarily cleared through the kidney thus nephrotoxicity and associated electrolyte disturbances are the most common side effects, reported at rates ranging from 1% to 5% of HIPEC administrations (Van Driel et al., 2018). Given the potential severity of cisplatin induced toxicities, many classes of protective agents have been used and investigated (Goel et al., 1989, Markowiak et al., 2019). Previous research has largely focused on concomitant administration of protective agents and chemotherapy (Dickey et al., 2005). While the onset of acute kidney injury (AKI) can be immediate, these effects can be durable. Less is known about the efficacy and utility of the renal protective agents when administered days after chemotherapy infusion. We present this case of management of cisplatin nephrotoxicity following HIPEC with delayed treatment with sodium thiosulfate (STS). This case suggests a new utility for this agent in rescue of severe cisplatin nephrotoxicity remote from infusion.
2 Case report
A fifty-two year old female with an advanced stage high grade mullerian adenocarcinoma presented from her medical oncologist for consideration of interval debulking surgery. Her history was notable for class III obesity (BMI 44), hypertension, type II diabetes mellitus, mild intermittent asthma, obstructive sleep apnea, bilateral pulmonary emboli, stage III chronic kidney disease, and history of prior right salpingo-oophorectomy for an endometrioma. The patient’s baseline creatinine was 1.2 mg/dL and glomerular filtration rate (GFR) was 50 mL/min.
She was initially diagnosed with a 34 × 24 × 33 cm partially necrotic pelvic mass and bilateral segmental and subsegmental pulmonary emboli. A biopsy revealed a high grade mullerian carcinoma. The patient received 6 cycles of neoadjuvant chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m2), with reduction in size of the dominant mass to 30 cm in largest dimension. Given a partial response to neoadjuvant chemotherapy, decision was made to proceed with an interval debulking and HIPEC. She underwent exploratory laparotomy, adhesiolysis, left salpingo-oophorectomy, upper vaginectomy, bilateral ureterolysis, supracolic omentectomy, optimal interval tumor debulking to no gross residual disease, ventral umbilical hernia repair, and HIPEC with cisplatin (100 mg/m2). Approximately 60 min prior to infusion of cisplatin intraperitoneally, the patient received 30 g of mannitol 20% intravenous solution over 1 h as well as 40 mg of furosemide intravenously. Intraoperatively, urine output was maintained above 100 mL per hour. The patient’s estimated blood loss was 700 mL and the patient was received 2 units of packed red blood cells (hemoglobin of 7.7 g/dL), 3 L of crystalloid, and 2 L of albumin
On arrival to the postoperative care unit, the patient was found to be hypotensive, with blood pressure of 88/54 mmHg, heart rate of 103 BPM, and temperature of 98.2°F. A repeat complete blood count (CBC) and complete metabolic profile (CMP) were obtained and the patient was admitted to the intensive care unit for resuscitation and close monitoring. Upon admission to the ICU, creatinine was elevated to 1.33 mg/dL, GFR of 42 mL/min, and hemoglobin was notably decreased to 6.5 g/dL. Her urine output was 160 mL per hour. She received 2 units of packed red blood cells and intravenous fluids were maintained at 30 mL/h. She was also started on a heparin drip for her history of bilateral pulmonary emboli.
On postoperative day 2, the patient’s vital signs improved, with blood pressure of 118/50 mmHg, heart rate of 87 BPM and respiratory rate of 18. Her total urine output was stable at 100 mL per hour and she was transferred to the standard postoperative floor. Although her hemoglobin and blood pressure remained normal, her creatinine continued to increase. At this time, she had met all other post-operative milestones including toleration of an oral diet, ambulation, and her pain was controlled. A fractional excretion of urea was obtained at that time and was consistent with intrinsic renal disease and differential diagnosis pointed to likely acute tubular necrosis due to acute hypotension postoperatively. Between post-operative days 3–4, her creatinine continued to increase up to 2.07 mg/dL and GFR reduced to 25 mL/min. Urine output remained normal. A renal ultrasound of the kidneys revealed no evidence of hydronephrosis and a manual urinalysis revealed absence of muddy brown casts. The patient’s creatinine continued to uptrend to 4.06 mg/dL and GFR decreased to 12 mL/min.
As her creatinine continued to increase and her repeat urinalysis was not consistent with acute tubular necrosis, cisplatin induced nephrotoxicity seemed to be the most likely etiology for her kidney injury. On postoperative day 7, the decision was made to administer sodium thiosulfate (STS) at 12 g/m2 over 6 h. On postoperative day 9 the creatinine increased to 4.4 g/dL. Thereafter, the patient’s creatinine began to decrease steadily until the day of discharge, on postoperative day 12, at which time the creatinine was 3.24 mg/dL and the GFR had improved to 15 mL/min. The patient continued to follow-up for weekly serum chemistries as an outpatient and creatinine and GFR continued to improve. As of her last follow-up, 6 weeks after surgery, the patient’s creatinine had returned to near baseline.
3 Discussion
Interval cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin has been shown to improve overall survival in advanced ovarian cancer patients as compared to surgical cytoreduction alone (Van Driel et al., 2018). The implementation of HIPEC programs is expanding at various institutions around the world, and thus the potential adverse effects are important to understand. In particular, cisplatin associated acute kidney injury is not uncommon, but can be mitigated (Chambers et al., 2020). Management concerning cisplatin renal failure in the literature is minimal.
HIPEC has a high risk of nephrotoxicity secondary to hypotension due to venous capacitance (Rotruck et al., 2014). Additionally, cisplatin induced nephrotoxicity is a commonly known side effect when administered intravenously, but can be aggravated in patients undergoing HIPEC.
Cisplatin administered via intraperitoneal route will remain in the bloodstream for approximately 5 days (Miller et al., 2010). As cisplatin accumulates in the kidneys, nephrotoxicity can occur several days following administration. Previous research demonstrates the benefit of sodium thiosulfate (STS) administration in patients receiving HIPEC for ovarian cancer (Miller et al., 2010). These benefits include a decrease in cisplatin induced nephrotoxicity and an increase in the dosage of cisplatin that could be given during HIPEC infusion. STS can bind and inactivate cisplatin in the kidneys to prevent cisplatin provoked and DNA damage mediated cell death (Laplace et al., 2020). More importantly, it can alleviate the cisplatin mediated damage to the mitochondria. Some studies indicate that STS concentrating in the kidneys can elevate to rapidly inactivate cisplatin (Miller et al., 2010).
STS has traditionally been administered either prior to or concomitantly with administration of cisplatin (Van Driel et al., 2018, Laplace et al., 2020). Other mitigation strategies for prevention of acute kidney injury include adequate hydration, furosemide and mannitol infusion during HIPEC to ensure adequate excretion and diuresis of cisplatin (Dickey et al., 2005). Currently there is no standard post-operative management of patients with cisplatin induced renal failure. Erdlenbruch et al. describe a case of a 14 year old pediatric patient who experienced ototoxicity and renal failure secondary to cisplatin overdose (Erdlenbruch et al., 2002). She was given a chemoprotective infusion of STS 6 days after the finding of the overdose. Urinary platinum excretion levels began to decrease following this infusion. This is similar to our case, where we saw a concomitant improvement in renal function as well as expanded diuresis.
This case demonstrates that, in the absence pre-renal and obstructive causes of AKI, STS can be used for cisplatin induced nephrotoxicity. Our case, which is the latest use of STS chemoprotection in the literature to our knowledge, shows that this mitigation strategy can be used many days after intraperitoneal cisplatin perfusion. While further studies are required to assess the timing with which STS is still effective in reducing cisplatin nephrotoxicity, our case does demonstrate its use as a rescue strategy to improve nephrotoxicity.
CRediT authorship contribution statement
K. Patel: Investigation, Writing - original draft, Writing - review & editing. A. Asare: Investigation, Writing - original draft, Writing - review & editing. S. Moufarrij: Investigation, Writing - original draft, Writing - review & editing. A.B. Costales: Investigation, Writing - original draft, Writing - review & editing, Conceptualization, Supervision.
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. | Recovering | ReactionOutcome | CC BY-NC-ND | 33732850 | 19,132,286 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Large intestine perforation'. | Amoebic colitis: A case series of a recurring missed diagnosis.
Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.
Introduction
Entamoeba histolytica (E. histolytica) is the pathogenic protozoan responsible for amoebic colitis, a common parasitic infection, 1 and the second leading cause of death from parasitic infections worldwide. 2 The clinical presentation of amoebic colitis is varied and may include cramping abdominal pain, watery and/or bloody diarrhea, weight loss, fever, and anemia. Complications such as toxic megacolon, perianal ulceration, and colonic perforation are described, 3 and extraintestinal complications may arise secondary to hematogenous spread to sites such as the liver, brain, and lungs. 3
We present a case series of four patients diagnosed with amoebic colitis. These cases highlight the importance of obtaining a thorough travel and exposure history, maintaining a high index of suspicion, and understanding the limitations of available investigations in order to differentiate amoebiasis from common differential diagnoses such as inflammatory bowel disease (IBD), bacterial colitis, and colorectal cancer. 3
Case series presentations
Case 1
A 36‐year‐old Indian woman with a medical history significant for thalassemia minor was diagnosed with ulcerative proctitis in India in May 2019. She was treated with sulfasalazine and corticosteroids. A flare of ulcerative colitis (UC) was documented following medication noncompliance, which settled with oral metronidazole prescribed by a local general practitioner. Following travel to Australia, her symptoms recurred and persisted for several months until she presented to hospital with bloody diarrhea, nausea, vomiting, and loss of weight; she was also noted to be 24 weeks' pregnant. Treatment with rectal and oral 5‐aminosalicylic acid and oral prednisolone was commenced with an initial improvement in symptoms. Given her pregnancy status and improvement with medical management, endoscopy was not performed. She subsequently re‐presented with severe bloody diarrhea associated with tachycardia, anemia (hemoglobin 76 g/L), and leukocytosis. Intravenous corticosteroids were commenced, and a sigmoidoscopy demonstrated Mayo 3 proctitis (Fig. 1a). Fecal microscopy and tissue histology both demonstrated E. histolytica organisms, consistent with amoebic colitis. Intravenous metronidazole (750 mg three times a day) and metronidazole suppositories were commenced with rapid resolution of rectal bleeding. She was discharged with a seven‐day course of oral metronidazole (400 mg three times a day) followed by paromomycin (500 mg three times a day). She remained well and delivered a healthy child at term.
Figure 1 (a) Severe proctitis in the rectum. (b) CT angiography (portal‐venous phase) demonstrating hypodense lesions scattered throughout the liver. (c) Inflammation and ulceration of the colon. (d) Histology of the sigmoid colon demonstrating Entamoeba histolytica organisms with ingested red cells (arrows). Credit: David Hugo Romero.
Case 2
A 75‐year‐old previously well man, on holiday from India, presented to hospital with a two‐week history of abdominal pain, fever, watery, nonbloody diarrhea and anorexia. On examination, he was tachycardic (heart rate 115 beats per minute), tachypneic (respiratory rate 28 breaths/min), and febrile (38.1°C). Abdominal examination revealed a soft abdomen with right iliac fossa tenderness. Initial laboratory findings demonstrated an elevated white cell count (39.2 × 109/L) and C‐reactive protein (CRP) (379 mg/L). A CT abdomen revealed a phlegmonous mass adjacent to the caecum, raising the possibility of appendicitis along with multiple ill‐defined hepatic lesions.
The patient underwent a laparotomy where a perforated caecal mass with peritonitis was found. Intraoperative colonoscopy demonstrated ulceration of the rectum and transverse colon, and a subtotal‐colectomy with end‐ileostomy was performed. Postoperatively, worsening transaminitis was noted, and a CT liver demonstrated innumerable hypodense hepatic lesions consistent with liver abscesses (Fig. 1b), which were subsequently biopsied. Human immunodeficiency virus (HIV), amoebic, and Echinococcus serology and Mycobacterial microscopy and culture were all negative.
Histology of the resected bowel demonstrated numerous E. histolytica organisms with ulceration and caecal perforation; cultures from other sites were negative for amoebiasis. The patient required serial drainage of hepatic abscesses and ultimately recovered following intravenous metronidazole and prolonged oral paromomycin.
Case 3
A 45‐year‐old healthy man presented with four weeks of worsening nonbloody diarrhea, 11 kg of weight loss, and a perianal abscess with a communicating anal fistula. Prior to admission, his general practitioner had treated him for suspected food poisoning and commenced oral metronidazole following a positive stool culture for Blastocystis hominis. The patient denied recent travel or receptive anal intercourse. In hospital, a fistulotomy was performed, and intravenous hydrocortisone and antibiotics were commenced for ongoing diarrhea. A sigmoidoscopy demonstrated an anal fistula and deep ulceration with rectal sparing. A presumptive diagnosis of Crohn's disease was made. Subsequent magnetic resonance enterography showed no small bowel involvement. The patient was transferred to a tertiary center following large‐volume rectal bleeding.
On arrival, the patient was anemic (hemoglobin 70 g/L) with an elevated CRP of 172 mg/L. Three fecal specimens were obtained and tested, and ova‐cyst‐parasite (OCP) analysis and amoebiasis, schistosomiasis, strongyloides, and syphilis serology were negative. A colonoscopy revealed moderate ileitis and multiple pancolonic serpiginous ulcers (Fig. 1c), further supporting a diagnosis of atypical ileocolonic and perianal Crohn's disease, and infliximab 10 mg/kg was commenced. Three days later, the patient deteriorated with fever and left iliac fossa pain. A CT abdomen demonstrated spontaneous sigmoid colon perforation with intraperitoneal free gas. He underwent an emergency laparotomy and Hartmann's procedure; histopathology demonstrated acute colitis and copious E. histolytica organisms (Fig. 1d). Intravenous metronidazole (750 mg tds) was commenced, and the patient made a full recovery.
Case 4
A 24‐year‐old Indian woman presented to hospital with a 10‐day history of abdominal pain, weight loss, and severe bloody diarrhea on a background of known UC. Her UC was diagnosed in India in 2018 and managed with mesalazine monotherapy.
On examination, vital signs were within normal limits, and abdominal examination revealed right‐sided involuntary guarding and tenderness. The patient was anemic (hemoglobin 93 g/L) with normal inflammatory markers. A CT abdomen showed rectal mucosal hyperenhancement. Intravenous hydrocortisone was commenced for a suspected UC flare, and a flexible sigmoidoscopy demonstrated Mayo 2 proctitis. HIV, hepatitis, and mycobacterium serology were negative. Stool microscopy was positive for E. histolytica organisms. Oral metronidazole followed by paromomycin were commenced, corticosteroids were weaned, and mesalazine was ceased. Bowel histology did not demonstrate amoebiasis.
Discussion
These cases highlight the challenges and pitfalls of diagnosing amoebic colitis in developed countries where the incidence is low. Significant variation in presenting symptoms, previous misdiagnosis, and amoebiasis masquerading as other common conditions all contribute to missed or late diagnoses, which can result in development of life‐threatening complications. In addition, these cases highlight the importance of a comprehensive travel history and maintaining an index of suspicion, even in patients with diagnosed IBD. We recommend that clinicians consider invasive amoebiasis in their list of differentials and be aware that it is both a local and imported disease. 1
E. histolytica infection begins with ingestion of cysts, typically through fecally contaminated water or food. In the small bowel, excystation occurs with the formation of mobile and invasive trophozoites, which aggregate in the mucin layer of the intestines, forming cysts and destroying colonic epithelium. 3 Approximately 90% of cases are self‐limiting and asymptomatic, 4 with spontaneous clearance of infection. 1 Symptoms of abdominal pain, watery and/or bloody diarrhea, weight loss, and fevers occur in 10% cases, and extraintestinal spread is noted in <1%. 4
E. histolytica is endemic to India, Southeast Asia, Egypt, and Mexico. 1 , 2 van Hal et al. reported that invasive amoebiasis has been prevalent in northern Australia, leading to locally acquired cases. 1 High‐risk populations in Australia include indigenous Australians, immigrants, residents returning from endemic countries, and men who have sex with men. 1 In this series, three of four patients had recently traveled to India; however, one case acquired E. histolytica despite no domestic or international travel. This has not previously been reported and illustrates the potential for local transmission.
Diagnostic tools for intestinal amoebiasis include: fecal microscopy, fecal polymerase chain reaction (PCR), fecal and/or serum antigen detection, serology, and histologic examination of colonic biopsy specimens. 5 Fecal microscopy is the most common first‐line investigation, particularly in developing countries; however, the sensitivity to identify cysts and/or trophozoites is suboptimal at 25–60%. 4 Given that organism excretion can vary, three specimens taken on separate days are recommended to increase the diagnostic yield. 5 Fecal PCR has a sensitivity >70% and a specificity >90%. 6 The sensitivity of antigen detection in feces is 90%, and in serum is 65% in the acute setting. 3 , 4 Detection of Entamoeba antibodies in serum is possible in 70–90% of individuals within 5–7 days of acute infection; however, this is not helpful in differentiating acute from previous infections. 3 , 4 , 5 Finally, colonic biopsy specimens are not considered a routine diagnostic tool, and visualization of amoeba is rare. Nonspecific histopathological findings such as hemorrhagic regions of the colon, flask‐shaped ulcerations, necrosis of intestinal wall, and focal perforation may be associated with amoebic colitis, and the diagnostic yield may be increased with specialized stains such as the periodic acid‐Schiff stain. 4
Despite these tools, diagnosis of amoebic colitis remains challenging. This is highlighted in Case 3, where serology and serial fecal cultures were negative, possibly as a result of a prior course of metronidazole. In two cases, diagnosis was made on bowel histology, which is not common, and only one case was diagnosed by noninvasive means. Other published series have documented the diagnostic challenges associated with amoebic colitis; however, the majority are from developing countries where the incidence is higher. Gupta et al. demonstrated a fatal case of amoebic colitis in India, in which a patient was misdiagnosed and treated for IBD before developing fulminant necrotizing amoebic colitis, leading to multiorgan failure and death. 7 Cases 2 and 3 in our cohort also demonstrate the dangers of delayed diagnosis as these patients required emergency laparotomy following colonic perforation. Den et al. also reported the difficulties of diagnosing amoebic colitis whereby repeated colonic biopsies and stool cultures were negative for E. histolytica; diagnosis was ultimately confirmed serologically with resolution of symptoms following appropriate antimicrobial therapy. 8 Finally, Tufail et al. described a case series of amoebic colitis in the United Kingdom masquerading as IBD. 9 Guidelines were suggested by the authors to screen for E. histolytica in all patients presenting with colitis, with amoebic antimicrobial cover to be empirically commenced in patients receiving immunosuppression until results are available. 9
The Australian Therapeutic Guidelines recommend treatment of acute amoebic colitis (dysentery) using metronidazole 600 mg orally every eight hours for seven days. 10 However, if severe (i.e. blood in the stools, perforation, peritonitis), then escalated doses of metronidazole of either 750 mg intravenously or 800 mg orally every eight hours for seven days are required. 10 Once treatment is completed, an intraluminal cyst eradication agent, paromomycin 500 mg orally, every eight hours for seven days, should be used. 10 Paromomycin prevents relapse given that treatment failure may occur in up to 40–60% of patients treated with metronidazole alone. 4
In conclusion, this case series highlights the challenges in diagnosing amoebic colitis and the potentially life‐threatening consequences of misdiagnosis, inappropriate immunosuppression, and delayed antimicrobial therapy.
Acknowledgements
We acknowledge David Hugo Romero for his contributions to the graphic design. | HYDROCORTISONE, INFLIXIMAB, METRONIDAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33732890 | 18,712,261 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Amoebic colitis: A case series of a recurring missed diagnosis.
Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.
Introduction
Entamoeba histolytica (E. histolytica) is the pathogenic protozoan responsible for amoebic colitis, a common parasitic infection, 1 and the second leading cause of death from parasitic infections worldwide. 2 The clinical presentation of amoebic colitis is varied and may include cramping abdominal pain, watery and/or bloody diarrhea, weight loss, fever, and anemia. Complications such as toxic megacolon, perianal ulceration, and colonic perforation are described, 3 and extraintestinal complications may arise secondary to hematogenous spread to sites such as the liver, brain, and lungs. 3
We present a case series of four patients diagnosed with amoebic colitis. These cases highlight the importance of obtaining a thorough travel and exposure history, maintaining a high index of suspicion, and understanding the limitations of available investigations in order to differentiate amoebiasis from common differential diagnoses such as inflammatory bowel disease (IBD), bacterial colitis, and colorectal cancer. 3
Case series presentations
Case 1
A 36‐year‐old Indian woman with a medical history significant for thalassemia minor was diagnosed with ulcerative proctitis in India in May 2019. She was treated with sulfasalazine and corticosteroids. A flare of ulcerative colitis (UC) was documented following medication noncompliance, which settled with oral metronidazole prescribed by a local general practitioner. Following travel to Australia, her symptoms recurred and persisted for several months until she presented to hospital with bloody diarrhea, nausea, vomiting, and loss of weight; she was also noted to be 24 weeks' pregnant. Treatment with rectal and oral 5‐aminosalicylic acid and oral prednisolone was commenced with an initial improvement in symptoms. Given her pregnancy status and improvement with medical management, endoscopy was not performed. She subsequently re‐presented with severe bloody diarrhea associated with tachycardia, anemia (hemoglobin 76 g/L), and leukocytosis. Intravenous corticosteroids were commenced, and a sigmoidoscopy demonstrated Mayo 3 proctitis (Fig. 1a). Fecal microscopy and tissue histology both demonstrated E. histolytica organisms, consistent with amoebic colitis. Intravenous metronidazole (750 mg three times a day) and metronidazole suppositories were commenced with rapid resolution of rectal bleeding. She was discharged with a seven‐day course of oral metronidazole (400 mg three times a day) followed by paromomycin (500 mg three times a day). She remained well and delivered a healthy child at term.
Figure 1 (a) Severe proctitis in the rectum. (b) CT angiography (portal‐venous phase) demonstrating hypodense lesions scattered throughout the liver. (c) Inflammation and ulceration of the colon. (d) Histology of the sigmoid colon demonstrating Entamoeba histolytica organisms with ingested red cells (arrows). Credit: David Hugo Romero.
Case 2
A 75‐year‐old previously well man, on holiday from India, presented to hospital with a two‐week history of abdominal pain, fever, watery, nonbloody diarrhea and anorexia. On examination, he was tachycardic (heart rate 115 beats per minute), tachypneic (respiratory rate 28 breaths/min), and febrile (38.1°C). Abdominal examination revealed a soft abdomen with right iliac fossa tenderness. Initial laboratory findings demonstrated an elevated white cell count (39.2 × 109/L) and C‐reactive protein (CRP) (379 mg/L). A CT abdomen revealed a phlegmonous mass adjacent to the caecum, raising the possibility of appendicitis along with multiple ill‐defined hepatic lesions.
The patient underwent a laparotomy where a perforated caecal mass with peritonitis was found. Intraoperative colonoscopy demonstrated ulceration of the rectum and transverse colon, and a subtotal‐colectomy with end‐ileostomy was performed. Postoperatively, worsening transaminitis was noted, and a CT liver demonstrated innumerable hypodense hepatic lesions consistent with liver abscesses (Fig. 1b), which were subsequently biopsied. Human immunodeficiency virus (HIV), amoebic, and Echinococcus serology and Mycobacterial microscopy and culture were all negative.
Histology of the resected bowel demonstrated numerous E. histolytica organisms with ulceration and caecal perforation; cultures from other sites were negative for amoebiasis. The patient required serial drainage of hepatic abscesses and ultimately recovered following intravenous metronidazole and prolonged oral paromomycin.
Case 3
A 45‐year‐old healthy man presented with four weeks of worsening nonbloody diarrhea, 11 kg of weight loss, and a perianal abscess with a communicating anal fistula. Prior to admission, his general practitioner had treated him for suspected food poisoning and commenced oral metronidazole following a positive stool culture for Blastocystis hominis. The patient denied recent travel or receptive anal intercourse. In hospital, a fistulotomy was performed, and intravenous hydrocortisone and antibiotics were commenced for ongoing diarrhea. A sigmoidoscopy demonstrated an anal fistula and deep ulceration with rectal sparing. A presumptive diagnosis of Crohn's disease was made. Subsequent magnetic resonance enterography showed no small bowel involvement. The patient was transferred to a tertiary center following large‐volume rectal bleeding.
On arrival, the patient was anemic (hemoglobin 70 g/L) with an elevated CRP of 172 mg/L. Three fecal specimens were obtained and tested, and ova‐cyst‐parasite (OCP) analysis and amoebiasis, schistosomiasis, strongyloides, and syphilis serology were negative. A colonoscopy revealed moderate ileitis and multiple pancolonic serpiginous ulcers (Fig. 1c), further supporting a diagnosis of atypical ileocolonic and perianal Crohn's disease, and infliximab 10 mg/kg was commenced. Three days later, the patient deteriorated with fever and left iliac fossa pain. A CT abdomen demonstrated spontaneous sigmoid colon perforation with intraperitoneal free gas. He underwent an emergency laparotomy and Hartmann's procedure; histopathology demonstrated acute colitis and copious E. histolytica organisms (Fig. 1d). Intravenous metronidazole (750 mg tds) was commenced, and the patient made a full recovery.
Case 4
A 24‐year‐old Indian woman presented to hospital with a 10‐day history of abdominal pain, weight loss, and severe bloody diarrhea on a background of known UC. Her UC was diagnosed in India in 2018 and managed with mesalazine monotherapy.
On examination, vital signs were within normal limits, and abdominal examination revealed right‐sided involuntary guarding and tenderness. The patient was anemic (hemoglobin 93 g/L) with normal inflammatory markers. A CT abdomen showed rectal mucosal hyperenhancement. Intravenous hydrocortisone was commenced for a suspected UC flare, and a flexible sigmoidoscopy demonstrated Mayo 2 proctitis. HIV, hepatitis, and mycobacterium serology were negative. Stool microscopy was positive for E. histolytica organisms. Oral metronidazole followed by paromomycin were commenced, corticosteroids were weaned, and mesalazine was ceased. Bowel histology did not demonstrate amoebiasis.
Discussion
These cases highlight the challenges and pitfalls of diagnosing amoebic colitis in developed countries where the incidence is low. Significant variation in presenting symptoms, previous misdiagnosis, and amoebiasis masquerading as other common conditions all contribute to missed or late diagnoses, which can result in development of life‐threatening complications. In addition, these cases highlight the importance of a comprehensive travel history and maintaining an index of suspicion, even in patients with diagnosed IBD. We recommend that clinicians consider invasive amoebiasis in their list of differentials and be aware that it is both a local and imported disease. 1
E. histolytica infection begins with ingestion of cysts, typically through fecally contaminated water or food. In the small bowel, excystation occurs with the formation of mobile and invasive trophozoites, which aggregate in the mucin layer of the intestines, forming cysts and destroying colonic epithelium. 3 Approximately 90% of cases are self‐limiting and asymptomatic, 4 with spontaneous clearance of infection. 1 Symptoms of abdominal pain, watery and/or bloody diarrhea, weight loss, and fevers occur in 10% cases, and extraintestinal spread is noted in <1%. 4
E. histolytica is endemic to India, Southeast Asia, Egypt, and Mexico. 1 , 2 van Hal et al. reported that invasive amoebiasis has been prevalent in northern Australia, leading to locally acquired cases. 1 High‐risk populations in Australia include indigenous Australians, immigrants, residents returning from endemic countries, and men who have sex with men. 1 In this series, three of four patients had recently traveled to India; however, one case acquired E. histolytica despite no domestic or international travel. This has not previously been reported and illustrates the potential for local transmission.
Diagnostic tools for intestinal amoebiasis include: fecal microscopy, fecal polymerase chain reaction (PCR), fecal and/or serum antigen detection, serology, and histologic examination of colonic biopsy specimens. 5 Fecal microscopy is the most common first‐line investigation, particularly in developing countries; however, the sensitivity to identify cysts and/or trophozoites is suboptimal at 25–60%. 4 Given that organism excretion can vary, three specimens taken on separate days are recommended to increase the diagnostic yield. 5 Fecal PCR has a sensitivity >70% and a specificity >90%. 6 The sensitivity of antigen detection in feces is 90%, and in serum is 65% in the acute setting. 3 , 4 Detection of Entamoeba antibodies in serum is possible in 70–90% of individuals within 5–7 days of acute infection; however, this is not helpful in differentiating acute from previous infections. 3 , 4 , 5 Finally, colonic biopsy specimens are not considered a routine diagnostic tool, and visualization of amoeba is rare. Nonspecific histopathological findings such as hemorrhagic regions of the colon, flask‐shaped ulcerations, necrosis of intestinal wall, and focal perforation may be associated with amoebic colitis, and the diagnostic yield may be increased with specialized stains such as the periodic acid‐Schiff stain. 4
Despite these tools, diagnosis of amoebic colitis remains challenging. This is highlighted in Case 3, where serology and serial fecal cultures were negative, possibly as a result of a prior course of metronidazole. In two cases, diagnosis was made on bowel histology, which is not common, and only one case was diagnosed by noninvasive means. Other published series have documented the diagnostic challenges associated with amoebic colitis; however, the majority are from developing countries where the incidence is higher. Gupta et al. demonstrated a fatal case of amoebic colitis in India, in which a patient was misdiagnosed and treated for IBD before developing fulminant necrotizing amoebic colitis, leading to multiorgan failure and death. 7 Cases 2 and 3 in our cohort also demonstrate the dangers of delayed diagnosis as these patients required emergency laparotomy following colonic perforation. Den et al. also reported the difficulties of diagnosing amoebic colitis whereby repeated colonic biopsies and stool cultures were negative for E. histolytica; diagnosis was ultimately confirmed serologically with resolution of symptoms following appropriate antimicrobial therapy. 8 Finally, Tufail et al. described a case series of amoebic colitis in the United Kingdom masquerading as IBD. 9 Guidelines were suggested by the authors to screen for E. histolytica in all patients presenting with colitis, with amoebic antimicrobial cover to be empirically commenced in patients receiving immunosuppression until results are available. 9
The Australian Therapeutic Guidelines recommend treatment of acute amoebic colitis (dysentery) using metronidazole 600 mg orally every eight hours for seven days. 10 However, if severe (i.e. blood in the stools, perforation, peritonitis), then escalated doses of metronidazole of either 750 mg intravenously or 800 mg orally every eight hours for seven days are required. 10 Once treatment is completed, an intraluminal cyst eradication agent, paromomycin 500 mg orally, every eight hours for seven days, should be used. 10 Paromomycin prevents relapse given that treatment failure may occur in up to 40–60% of patients treated with metronidazole alone. 4
In conclusion, this case series highlights the challenges in diagnosing amoebic colitis and the potentially life‐threatening consequences of misdiagnosis, inappropriate immunosuppression, and delayed antimicrobial therapy.
Acknowledgements
We acknowledge David Hugo Romero for his contributions to the graphic design. | HYDROCORTISONE, INFLIXIMAB, METRONIDAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33732890 | 18,712,261 | 2021-03 |
What was the administration route of drug 'HYDROCORTISONE'? | Amoebic colitis: A case series of a recurring missed diagnosis.
Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.
Introduction
Entamoeba histolytica (E. histolytica) is the pathogenic protozoan responsible for amoebic colitis, a common parasitic infection, 1 and the second leading cause of death from parasitic infections worldwide. 2 The clinical presentation of amoebic colitis is varied and may include cramping abdominal pain, watery and/or bloody diarrhea, weight loss, fever, and anemia. Complications such as toxic megacolon, perianal ulceration, and colonic perforation are described, 3 and extraintestinal complications may arise secondary to hematogenous spread to sites such as the liver, brain, and lungs. 3
We present a case series of four patients diagnosed with amoebic colitis. These cases highlight the importance of obtaining a thorough travel and exposure history, maintaining a high index of suspicion, and understanding the limitations of available investigations in order to differentiate amoebiasis from common differential diagnoses such as inflammatory bowel disease (IBD), bacterial colitis, and colorectal cancer. 3
Case series presentations
Case 1
A 36‐year‐old Indian woman with a medical history significant for thalassemia minor was diagnosed with ulcerative proctitis in India in May 2019. She was treated with sulfasalazine and corticosteroids. A flare of ulcerative colitis (UC) was documented following medication noncompliance, which settled with oral metronidazole prescribed by a local general practitioner. Following travel to Australia, her symptoms recurred and persisted for several months until she presented to hospital with bloody diarrhea, nausea, vomiting, and loss of weight; she was also noted to be 24 weeks' pregnant. Treatment with rectal and oral 5‐aminosalicylic acid and oral prednisolone was commenced with an initial improvement in symptoms. Given her pregnancy status and improvement with medical management, endoscopy was not performed. She subsequently re‐presented with severe bloody diarrhea associated with tachycardia, anemia (hemoglobin 76 g/L), and leukocytosis. Intravenous corticosteroids were commenced, and a sigmoidoscopy demonstrated Mayo 3 proctitis (Fig. 1a). Fecal microscopy and tissue histology both demonstrated E. histolytica organisms, consistent with amoebic colitis. Intravenous metronidazole (750 mg three times a day) and metronidazole suppositories were commenced with rapid resolution of rectal bleeding. She was discharged with a seven‐day course of oral metronidazole (400 mg three times a day) followed by paromomycin (500 mg three times a day). She remained well and delivered a healthy child at term.
Figure 1 (a) Severe proctitis in the rectum. (b) CT angiography (portal‐venous phase) demonstrating hypodense lesions scattered throughout the liver. (c) Inflammation and ulceration of the colon. (d) Histology of the sigmoid colon demonstrating Entamoeba histolytica organisms with ingested red cells (arrows). Credit: David Hugo Romero.
Case 2
A 75‐year‐old previously well man, on holiday from India, presented to hospital with a two‐week history of abdominal pain, fever, watery, nonbloody diarrhea and anorexia. On examination, he was tachycardic (heart rate 115 beats per minute), tachypneic (respiratory rate 28 breaths/min), and febrile (38.1°C). Abdominal examination revealed a soft abdomen with right iliac fossa tenderness. Initial laboratory findings demonstrated an elevated white cell count (39.2 × 109/L) and C‐reactive protein (CRP) (379 mg/L). A CT abdomen revealed a phlegmonous mass adjacent to the caecum, raising the possibility of appendicitis along with multiple ill‐defined hepatic lesions.
The patient underwent a laparotomy where a perforated caecal mass with peritonitis was found. Intraoperative colonoscopy demonstrated ulceration of the rectum and transverse colon, and a subtotal‐colectomy with end‐ileostomy was performed. Postoperatively, worsening transaminitis was noted, and a CT liver demonstrated innumerable hypodense hepatic lesions consistent with liver abscesses (Fig. 1b), which were subsequently biopsied. Human immunodeficiency virus (HIV), amoebic, and Echinococcus serology and Mycobacterial microscopy and culture were all negative.
Histology of the resected bowel demonstrated numerous E. histolytica organisms with ulceration and caecal perforation; cultures from other sites were negative for amoebiasis. The patient required serial drainage of hepatic abscesses and ultimately recovered following intravenous metronidazole and prolonged oral paromomycin.
Case 3
A 45‐year‐old healthy man presented with four weeks of worsening nonbloody diarrhea, 11 kg of weight loss, and a perianal abscess with a communicating anal fistula. Prior to admission, his general practitioner had treated him for suspected food poisoning and commenced oral metronidazole following a positive stool culture for Blastocystis hominis. The patient denied recent travel or receptive anal intercourse. In hospital, a fistulotomy was performed, and intravenous hydrocortisone and antibiotics were commenced for ongoing diarrhea. A sigmoidoscopy demonstrated an anal fistula and deep ulceration with rectal sparing. A presumptive diagnosis of Crohn's disease was made. Subsequent magnetic resonance enterography showed no small bowel involvement. The patient was transferred to a tertiary center following large‐volume rectal bleeding.
On arrival, the patient was anemic (hemoglobin 70 g/L) with an elevated CRP of 172 mg/L. Three fecal specimens were obtained and tested, and ova‐cyst‐parasite (OCP) analysis and amoebiasis, schistosomiasis, strongyloides, and syphilis serology were negative. A colonoscopy revealed moderate ileitis and multiple pancolonic serpiginous ulcers (Fig. 1c), further supporting a diagnosis of atypical ileocolonic and perianal Crohn's disease, and infliximab 10 mg/kg was commenced. Three days later, the patient deteriorated with fever and left iliac fossa pain. A CT abdomen demonstrated spontaneous sigmoid colon perforation with intraperitoneal free gas. He underwent an emergency laparotomy and Hartmann's procedure; histopathology demonstrated acute colitis and copious E. histolytica organisms (Fig. 1d). Intravenous metronidazole (750 mg tds) was commenced, and the patient made a full recovery.
Case 4
A 24‐year‐old Indian woman presented to hospital with a 10‐day history of abdominal pain, weight loss, and severe bloody diarrhea on a background of known UC. Her UC was diagnosed in India in 2018 and managed with mesalazine monotherapy.
On examination, vital signs were within normal limits, and abdominal examination revealed right‐sided involuntary guarding and tenderness. The patient was anemic (hemoglobin 93 g/L) with normal inflammatory markers. A CT abdomen showed rectal mucosal hyperenhancement. Intravenous hydrocortisone was commenced for a suspected UC flare, and a flexible sigmoidoscopy demonstrated Mayo 2 proctitis. HIV, hepatitis, and mycobacterium serology were negative. Stool microscopy was positive for E. histolytica organisms. Oral metronidazole followed by paromomycin were commenced, corticosteroids were weaned, and mesalazine was ceased. Bowel histology did not demonstrate amoebiasis.
Discussion
These cases highlight the challenges and pitfalls of diagnosing amoebic colitis in developed countries where the incidence is low. Significant variation in presenting symptoms, previous misdiagnosis, and amoebiasis masquerading as other common conditions all contribute to missed or late diagnoses, which can result in development of life‐threatening complications. In addition, these cases highlight the importance of a comprehensive travel history and maintaining an index of suspicion, even in patients with diagnosed IBD. We recommend that clinicians consider invasive amoebiasis in their list of differentials and be aware that it is both a local and imported disease. 1
E. histolytica infection begins with ingestion of cysts, typically through fecally contaminated water or food. In the small bowel, excystation occurs with the formation of mobile and invasive trophozoites, which aggregate in the mucin layer of the intestines, forming cysts and destroying colonic epithelium. 3 Approximately 90% of cases are self‐limiting and asymptomatic, 4 with spontaneous clearance of infection. 1 Symptoms of abdominal pain, watery and/or bloody diarrhea, weight loss, and fevers occur in 10% cases, and extraintestinal spread is noted in <1%. 4
E. histolytica is endemic to India, Southeast Asia, Egypt, and Mexico. 1 , 2 van Hal et al. reported that invasive amoebiasis has been prevalent in northern Australia, leading to locally acquired cases. 1 High‐risk populations in Australia include indigenous Australians, immigrants, residents returning from endemic countries, and men who have sex with men. 1 In this series, three of four patients had recently traveled to India; however, one case acquired E. histolytica despite no domestic or international travel. This has not previously been reported and illustrates the potential for local transmission.
Diagnostic tools for intestinal amoebiasis include: fecal microscopy, fecal polymerase chain reaction (PCR), fecal and/or serum antigen detection, serology, and histologic examination of colonic biopsy specimens. 5 Fecal microscopy is the most common first‐line investigation, particularly in developing countries; however, the sensitivity to identify cysts and/or trophozoites is suboptimal at 25–60%. 4 Given that organism excretion can vary, three specimens taken on separate days are recommended to increase the diagnostic yield. 5 Fecal PCR has a sensitivity >70% and a specificity >90%. 6 The sensitivity of antigen detection in feces is 90%, and in serum is 65% in the acute setting. 3 , 4 Detection of Entamoeba antibodies in serum is possible in 70–90% of individuals within 5–7 days of acute infection; however, this is not helpful in differentiating acute from previous infections. 3 , 4 , 5 Finally, colonic biopsy specimens are not considered a routine diagnostic tool, and visualization of amoeba is rare. Nonspecific histopathological findings such as hemorrhagic regions of the colon, flask‐shaped ulcerations, necrosis of intestinal wall, and focal perforation may be associated with amoebic colitis, and the diagnostic yield may be increased with specialized stains such as the periodic acid‐Schiff stain. 4
Despite these tools, diagnosis of amoebic colitis remains challenging. This is highlighted in Case 3, where serology and serial fecal cultures were negative, possibly as a result of a prior course of metronidazole. In two cases, diagnosis was made on bowel histology, which is not common, and only one case was diagnosed by noninvasive means. Other published series have documented the diagnostic challenges associated with amoebic colitis; however, the majority are from developing countries where the incidence is higher. Gupta et al. demonstrated a fatal case of amoebic colitis in India, in which a patient was misdiagnosed and treated for IBD before developing fulminant necrotizing amoebic colitis, leading to multiorgan failure and death. 7 Cases 2 and 3 in our cohort also demonstrate the dangers of delayed diagnosis as these patients required emergency laparotomy following colonic perforation. Den et al. also reported the difficulties of diagnosing amoebic colitis whereby repeated colonic biopsies and stool cultures were negative for E. histolytica; diagnosis was ultimately confirmed serologically with resolution of symptoms following appropriate antimicrobial therapy. 8 Finally, Tufail et al. described a case series of amoebic colitis in the United Kingdom masquerading as IBD. 9 Guidelines were suggested by the authors to screen for E. histolytica in all patients presenting with colitis, with amoebic antimicrobial cover to be empirically commenced in patients receiving immunosuppression until results are available. 9
The Australian Therapeutic Guidelines recommend treatment of acute amoebic colitis (dysentery) using metronidazole 600 mg orally every eight hours for seven days. 10 However, if severe (i.e. blood in the stools, perforation, peritonitis), then escalated doses of metronidazole of either 750 mg intravenously or 800 mg orally every eight hours for seven days are required. 10 Once treatment is completed, an intraluminal cyst eradication agent, paromomycin 500 mg orally, every eight hours for seven days, should be used. 10 Paromomycin prevents relapse given that treatment failure may occur in up to 40–60% of patients treated with metronidazole alone. 4
In conclusion, this case series highlights the challenges in diagnosing amoebic colitis and the potentially life‐threatening consequences of misdiagnosis, inappropriate immunosuppression, and delayed antimicrobial therapy.
Acknowledgements
We acknowledge David Hugo Romero for his contributions to the graphic design. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33732890 | 18,712,261 | 2021-03 |
What was the dosage of drug 'HYDROCORTISONE'? | Amoebic colitis: A case series of a recurring missed diagnosis.
Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.
Introduction
Entamoeba histolytica (E. histolytica) is the pathogenic protozoan responsible for amoebic colitis, a common parasitic infection, 1 and the second leading cause of death from parasitic infections worldwide. 2 The clinical presentation of amoebic colitis is varied and may include cramping abdominal pain, watery and/or bloody diarrhea, weight loss, fever, and anemia. Complications such as toxic megacolon, perianal ulceration, and colonic perforation are described, 3 and extraintestinal complications may arise secondary to hematogenous spread to sites such as the liver, brain, and lungs. 3
We present a case series of four patients diagnosed with amoebic colitis. These cases highlight the importance of obtaining a thorough travel and exposure history, maintaining a high index of suspicion, and understanding the limitations of available investigations in order to differentiate amoebiasis from common differential diagnoses such as inflammatory bowel disease (IBD), bacterial colitis, and colorectal cancer. 3
Case series presentations
Case 1
A 36‐year‐old Indian woman with a medical history significant for thalassemia minor was diagnosed with ulcerative proctitis in India in May 2019. She was treated with sulfasalazine and corticosteroids. A flare of ulcerative colitis (UC) was documented following medication noncompliance, which settled with oral metronidazole prescribed by a local general practitioner. Following travel to Australia, her symptoms recurred and persisted for several months until she presented to hospital with bloody diarrhea, nausea, vomiting, and loss of weight; she was also noted to be 24 weeks' pregnant. Treatment with rectal and oral 5‐aminosalicylic acid and oral prednisolone was commenced with an initial improvement in symptoms. Given her pregnancy status and improvement with medical management, endoscopy was not performed. She subsequently re‐presented with severe bloody diarrhea associated with tachycardia, anemia (hemoglobin 76 g/L), and leukocytosis. Intravenous corticosteroids were commenced, and a sigmoidoscopy demonstrated Mayo 3 proctitis (Fig. 1a). Fecal microscopy and tissue histology both demonstrated E. histolytica organisms, consistent with amoebic colitis. Intravenous metronidazole (750 mg three times a day) and metronidazole suppositories were commenced with rapid resolution of rectal bleeding. She was discharged with a seven‐day course of oral metronidazole (400 mg three times a day) followed by paromomycin (500 mg three times a day). She remained well and delivered a healthy child at term.
Figure 1 (a) Severe proctitis in the rectum. (b) CT angiography (portal‐venous phase) demonstrating hypodense lesions scattered throughout the liver. (c) Inflammation and ulceration of the colon. (d) Histology of the sigmoid colon demonstrating Entamoeba histolytica organisms with ingested red cells (arrows). Credit: David Hugo Romero.
Case 2
A 75‐year‐old previously well man, on holiday from India, presented to hospital with a two‐week history of abdominal pain, fever, watery, nonbloody diarrhea and anorexia. On examination, he was tachycardic (heart rate 115 beats per minute), tachypneic (respiratory rate 28 breaths/min), and febrile (38.1°C). Abdominal examination revealed a soft abdomen with right iliac fossa tenderness. Initial laboratory findings demonstrated an elevated white cell count (39.2 × 109/L) and C‐reactive protein (CRP) (379 mg/L). A CT abdomen revealed a phlegmonous mass adjacent to the caecum, raising the possibility of appendicitis along with multiple ill‐defined hepatic lesions.
The patient underwent a laparotomy where a perforated caecal mass with peritonitis was found. Intraoperative colonoscopy demonstrated ulceration of the rectum and transverse colon, and a subtotal‐colectomy with end‐ileostomy was performed. Postoperatively, worsening transaminitis was noted, and a CT liver demonstrated innumerable hypodense hepatic lesions consistent with liver abscesses (Fig. 1b), which were subsequently biopsied. Human immunodeficiency virus (HIV), amoebic, and Echinococcus serology and Mycobacterial microscopy and culture were all negative.
Histology of the resected bowel demonstrated numerous E. histolytica organisms with ulceration and caecal perforation; cultures from other sites were negative for amoebiasis. The patient required serial drainage of hepatic abscesses and ultimately recovered following intravenous metronidazole and prolonged oral paromomycin.
Case 3
A 45‐year‐old healthy man presented with four weeks of worsening nonbloody diarrhea, 11 kg of weight loss, and a perianal abscess with a communicating anal fistula. Prior to admission, his general practitioner had treated him for suspected food poisoning and commenced oral metronidazole following a positive stool culture for Blastocystis hominis. The patient denied recent travel or receptive anal intercourse. In hospital, a fistulotomy was performed, and intravenous hydrocortisone and antibiotics were commenced for ongoing diarrhea. A sigmoidoscopy demonstrated an anal fistula and deep ulceration with rectal sparing. A presumptive diagnosis of Crohn's disease was made. Subsequent magnetic resonance enterography showed no small bowel involvement. The patient was transferred to a tertiary center following large‐volume rectal bleeding.
On arrival, the patient was anemic (hemoglobin 70 g/L) with an elevated CRP of 172 mg/L. Three fecal specimens were obtained and tested, and ova‐cyst‐parasite (OCP) analysis and amoebiasis, schistosomiasis, strongyloides, and syphilis serology were negative. A colonoscopy revealed moderate ileitis and multiple pancolonic serpiginous ulcers (Fig. 1c), further supporting a diagnosis of atypical ileocolonic and perianal Crohn's disease, and infliximab 10 mg/kg was commenced. Three days later, the patient deteriorated with fever and left iliac fossa pain. A CT abdomen demonstrated spontaneous sigmoid colon perforation with intraperitoneal free gas. He underwent an emergency laparotomy and Hartmann's procedure; histopathology demonstrated acute colitis and copious E. histolytica organisms (Fig. 1d). Intravenous metronidazole (750 mg tds) was commenced, and the patient made a full recovery.
Case 4
A 24‐year‐old Indian woman presented to hospital with a 10‐day history of abdominal pain, weight loss, and severe bloody diarrhea on a background of known UC. Her UC was diagnosed in India in 2018 and managed with mesalazine monotherapy.
On examination, vital signs were within normal limits, and abdominal examination revealed right‐sided involuntary guarding and tenderness. The patient was anemic (hemoglobin 93 g/L) with normal inflammatory markers. A CT abdomen showed rectal mucosal hyperenhancement. Intravenous hydrocortisone was commenced for a suspected UC flare, and a flexible sigmoidoscopy demonstrated Mayo 2 proctitis. HIV, hepatitis, and mycobacterium serology were negative. Stool microscopy was positive for E. histolytica organisms. Oral metronidazole followed by paromomycin were commenced, corticosteroids were weaned, and mesalazine was ceased. Bowel histology did not demonstrate amoebiasis.
Discussion
These cases highlight the challenges and pitfalls of diagnosing amoebic colitis in developed countries where the incidence is low. Significant variation in presenting symptoms, previous misdiagnosis, and amoebiasis masquerading as other common conditions all contribute to missed or late diagnoses, which can result in development of life‐threatening complications. In addition, these cases highlight the importance of a comprehensive travel history and maintaining an index of suspicion, even in patients with diagnosed IBD. We recommend that clinicians consider invasive amoebiasis in their list of differentials and be aware that it is both a local and imported disease. 1
E. histolytica infection begins with ingestion of cysts, typically through fecally contaminated water or food. In the small bowel, excystation occurs with the formation of mobile and invasive trophozoites, which aggregate in the mucin layer of the intestines, forming cysts and destroying colonic epithelium. 3 Approximately 90% of cases are self‐limiting and asymptomatic, 4 with spontaneous clearance of infection. 1 Symptoms of abdominal pain, watery and/or bloody diarrhea, weight loss, and fevers occur in 10% cases, and extraintestinal spread is noted in <1%. 4
E. histolytica is endemic to India, Southeast Asia, Egypt, and Mexico. 1 , 2 van Hal et al. reported that invasive amoebiasis has been prevalent in northern Australia, leading to locally acquired cases. 1 High‐risk populations in Australia include indigenous Australians, immigrants, residents returning from endemic countries, and men who have sex with men. 1 In this series, three of four patients had recently traveled to India; however, one case acquired E. histolytica despite no domestic or international travel. This has not previously been reported and illustrates the potential for local transmission.
Diagnostic tools for intestinal amoebiasis include: fecal microscopy, fecal polymerase chain reaction (PCR), fecal and/or serum antigen detection, serology, and histologic examination of colonic biopsy specimens. 5 Fecal microscopy is the most common first‐line investigation, particularly in developing countries; however, the sensitivity to identify cysts and/or trophozoites is suboptimal at 25–60%. 4 Given that organism excretion can vary, three specimens taken on separate days are recommended to increase the diagnostic yield. 5 Fecal PCR has a sensitivity >70% and a specificity >90%. 6 The sensitivity of antigen detection in feces is 90%, and in serum is 65% in the acute setting. 3 , 4 Detection of Entamoeba antibodies in serum is possible in 70–90% of individuals within 5–7 days of acute infection; however, this is not helpful in differentiating acute from previous infections. 3 , 4 , 5 Finally, colonic biopsy specimens are not considered a routine diagnostic tool, and visualization of amoeba is rare. Nonspecific histopathological findings such as hemorrhagic regions of the colon, flask‐shaped ulcerations, necrosis of intestinal wall, and focal perforation may be associated with amoebic colitis, and the diagnostic yield may be increased with specialized stains such as the periodic acid‐Schiff stain. 4
Despite these tools, diagnosis of amoebic colitis remains challenging. This is highlighted in Case 3, where serology and serial fecal cultures were negative, possibly as a result of a prior course of metronidazole. In two cases, diagnosis was made on bowel histology, which is not common, and only one case was diagnosed by noninvasive means. Other published series have documented the diagnostic challenges associated with amoebic colitis; however, the majority are from developing countries where the incidence is higher. Gupta et al. demonstrated a fatal case of amoebic colitis in India, in which a patient was misdiagnosed and treated for IBD before developing fulminant necrotizing amoebic colitis, leading to multiorgan failure and death. 7 Cases 2 and 3 in our cohort also demonstrate the dangers of delayed diagnosis as these patients required emergency laparotomy following colonic perforation. Den et al. also reported the difficulties of diagnosing amoebic colitis whereby repeated colonic biopsies and stool cultures were negative for E. histolytica; diagnosis was ultimately confirmed serologically with resolution of symptoms following appropriate antimicrobial therapy. 8 Finally, Tufail et al. described a case series of amoebic colitis in the United Kingdom masquerading as IBD. 9 Guidelines were suggested by the authors to screen for E. histolytica in all patients presenting with colitis, with amoebic antimicrobial cover to be empirically commenced in patients receiving immunosuppression until results are available. 9
The Australian Therapeutic Guidelines recommend treatment of acute amoebic colitis (dysentery) using metronidazole 600 mg orally every eight hours for seven days. 10 However, if severe (i.e. blood in the stools, perforation, peritonitis), then escalated doses of metronidazole of either 750 mg intravenously or 800 mg orally every eight hours for seven days are required. 10 Once treatment is completed, an intraluminal cyst eradication agent, paromomycin 500 mg orally, every eight hours for seven days, should be used. 10 Paromomycin prevents relapse given that treatment failure may occur in up to 40–60% of patients treated with metronidazole alone. 4
In conclusion, this case series highlights the challenges in diagnosing amoebic colitis and the potentially life‐threatening consequences of misdiagnosis, inappropriate immunosuppression, and delayed antimicrobial therapy.
Acknowledgements
We acknowledge David Hugo Romero for his contributions to the graphic design. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33732890 | 18,712,261 | 2021-03 |
What was the dosage of drug 'METRONIDAZOLE'? | Amoebic colitis: A case series of a recurring missed diagnosis.
Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.
Introduction
Entamoeba histolytica (E. histolytica) is the pathogenic protozoan responsible for amoebic colitis, a common parasitic infection, 1 and the second leading cause of death from parasitic infections worldwide. 2 The clinical presentation of amoebic colitis is varied and may include cramping abdominal pain, watery and/or bloody diarrhea, weight loss, fever, and anemia. Complications such as toxic megacolon, perianal ulceration, and colonic perforation are described, 3 and extraintestinal complications may arise secondary to hematogenous spread to sites such as the liver, brain, and lungs. 3
We present a case series of four patients diagnosed with amoebic colitis. These cases highlight the importance of obtaining a thorough travel and exposure history, maintaining a high index of suspicion, and understanding the limitations of available investigations in order to differentiate amoebiasis from common differential diagnoses such as inflammatory bowel disease (IBD), bacterial colitis, and colorectal cancer. 3
Case series presentations
Case 1
A 36‐year‐old Indian woman with a medical history significant for thalassemia minor was diagnosed with ulcerative proctitis in India in May 2019. She was treated with sulfasalazine and corticosteroids. A flare of ulcerative colitis (UC) was documented following medication noncompliance, which settled with oral metronidazole prescribed by a local general practitioner. Following travel to Australia, her symptoms recurred and persisted for several months until she presented to hospital with bloody diarrhea, nausea, vomiting, and loss of weight; she was also noted to be 24 weeks' pregnant. Treatment with rectal and oral 5‐aminosalicylic acid and oral prednisolone was commenced with an initial improvement in symptoms. Given her pregnancy status and improvement with medical management, endoscopy was not performed. She subsequently re‐presented with severe bloody diarrhea associated with tachycardia, anemia (hemoglobin 76 g/L), and leukocytosis. Intravenous corticosteroids were commenced, and a sigmoidoscopy demonstrated Mayo 3 proctitis (Fig. 1a). Fecal microscopy and tissue histology both demonstrated E. histolytica organisms, consistent with amoebic colitis. Intravenous metronidazole (750 mg three times a day) and metronidazole suppositories were commenced with rapid resolution of rectal bleeding. She was discharged with a seven‐day course of oral metronidazole (400 mg three times a day) followed by paromomycin (500 mg three times a day). She remained well and delivered a healthy child at term.
Figure 1 (a) Severe proctitis in the rectum. (b) CT angiography (portal‐venous phase) demonstrating hypodense lesions scattered throughout the liver. (c) Inflammation and ulceration of the colon. (d) Histology of the sigmoid colon demonstrating Entamoeba histolytica organisms with ingested red cells (arrows). Credit: David Hugo Romero.
Case 2
A 75‐year‐old previously well man, on holiday from India, presented to hospital with a two‐week history of abdominal pain, fever, watery, nonbloody diarrhea and anorexia. On examination, he was tachycardic (heart rate 115 beats per minute), tachypneic (respiratory rate 28 breaths/min), and febrile (38.1°C). Abdominal examination revealed a soft abdomen with right iliac fossa tenderness. Initial laboratory findings demonstrated an elevated white cell count (39.2 × 109/L) and C‐reactive protein (CRP) (379 mg/L). A CT abdomen revealed a phlegmonous mass adjacent to the caecum, raising the possibility of appendicitis along with multiple ill‐defined hepatic lesions.
The patient underwent a laparotomy where a perforated caecal mass with peritonitis was found. Intraoperative colonoscopy demonstrated ulceration of the rectum and transverse colon, and a subtotal‐colectomy with end‐ileostomy was performed. Postoperatively, worsening transaminitis was noted, and a CT liver demonstrated innumerable hypodense hepatic lesions consistent with liver abscesses (Fig. 1b), which were subsequently biopsied. Human immunodeficiency virus (HIV), amoebic, and Echinococcus serology and Mycobacterial microscopy and culture were all negative.
Histology of the resected bowel demonstrated numerous E. histolytica organisms with ulceration and caecal perforation; cultures from other sites were negative for amoebiasis. The patient required serial drainage of hepatic abscesses and ultimately recovered following intravenous metronidazole and prolonged oral paromomycin.
Case 3
A 45‐year‐old healthy man presented with four weeks of worsening nonbloody diarrhea, 11 kg of weight loss, and a perianal abscess with a communicating anal fistula. Prior to admission, his general practitioner had treated him for suspected food poisoning and commenced oral metronidazole following a positive stool culture for Blastocystis hominis. The patient denied recent travel or receptive anal intercourse. In hospital, a fistulotomy was performed, and intravenous hydrocortisone and antibiotics were commenced for ongoing diarrhea. A sigmoidoscopy demonstrated an anal fistula and deep ulceration with rectal sparing. A presumptive diagnosis of Crohn's disease was made. Subsequent magnetic resonance enterography showed no small bowel involvement. The patient was transferred to a tertiary center following large‐volume rectal bleeding.
On arrival, the patient was anemic (hemoglobin 70 g/L) with an elevated CRP of 172 mg/L. Three fecal specimens were obtained and tested, and ova‐cyst‐parasite (OCP) analysis and amoebiasis, schistosomiasis, strongyloides, and syphilis serology were negative. A colonoscopy revealed moderate ileitis and multiple pancolonic serpiginous ulcers (Fig. 1c), further supporting a diagnosis of atypical ileocolonic and perianal Crohn's disease, and infliximab 10 mg/kg was commenced. Three days later, the patient deteriorated with fever and left iliac fossa pain. A CT abdomen demonstrated spontaneous sigmoid colon perforation with intraperitoneal free gas. He underwent an emergency laparotomy and Hartmann's procedure; histopathology demonstrated acute colitis and copious E. histolytica organisms (Fig. 1d). Intravenous metronidazole (750 mg tds) was commenced, and the patient made a full recovery.
Case 4
A 24‐year‐old Indian woman presented to hospital with a 10‐day history of abdominal pain, weight loss, and severe bloody diarrhea on a background of known UC. Her UC was diagnosed in India in 2018 and managed with mesalazine monotherapy.
On examination, vital signs were within normal limits, and abdominal examination revealed right‐sided involuntary guarding and tenderness. The patient was anemic (hemoglobin 93 g/L) with normal inflammatory markers. A CT abdomen showed rectal mucosal hyperenhancement. Intravenous hydrocortisone was commenced for a suspected UC flare, and a flexible sigmoidoscopy demonstrated Mayo 2 proctitis. HIV, hepatitis, and mycobacterium serology were negative. Stool microscopy was positive for E. histolytica organisms. Oral metronidazole followed by paromomycin were commenced, corticosteroids were weaned, and mesalazine was ceased. Bowel histology did not demonstrate amoebiasis.
Discussion
These cases highlight the challenges and pitfalls of diagnosing amoebic colitis in developed countries where the incidence is low. Significant variation in presenting symptoms, previous misdiagnosis, and amoebiasis masquerading as other common conditions all contribute to missed or late diagnoses, which can result in development of life‐threatening complications. In addition, these cases highlight the importance of a comprehensive travel history and maintaining an index of suspicion, even in patients with diagnosed IBD. We recommend that clinicians consider invasive amoebiasis in their list of differentials and be aware that it is both a local and imported disease. 1
E. histolytica infection begins with ingestion of cysts, typically through fecally contaminated water or food. In the small bowel, excystation occurs with the formation of mobile and invasive trophozoites, which aggregate in the mucin layer of the intestines, forming cysts and destroying colonic epithelium. 3 Approximately 90% of cases are self‐limiting and asymptomatic, 4 with spontaneous clearance of infection. 1 Symptoms of abdominal pain, watery and/or bloody diarrhea, weight loss, and fevers occur in 10% cases, and extraintestinal spread is noted in <1%. 4
E. histolytica is endemic to India, Southeast Asia, Egypt, and Mexico. 1 , 2 van Hal et al. reported that invasive amoebiasis has been prevalent in northern Australia, leading to locally acquired cases. 1 High‐risk populations in Australia include indigenous Australians, immigrants, residents returning from endemic countries, and men who have sex with men. 1 In this series, three of four patients had recently traveled to India; however, one case acquired E. histolytica despite no domestic or international travel. This has not previously been reported and illustrates the potential for local transmission.
Diagnostic tools for intestinal amoebiasis include: fecal microscopy, fecal polymerase chain reaction (PCR), fecal and/or serum antigen detection, serology, and histologic examination of colonic biopsy specimens. 5 Fecal microscopy is the most common first‐line investigation, particularly in developing countries; however, the sensitivity to identify cysts and/or trophozoites is suboptimal at 25–60%. 4 Given that organism excretion can vary, three specimens taken on separate days are recommended to increase the diagnostic yield. 5 Fecal PCR has a sensitivity >70% and a specificity >90%. 6 The sensitivity of antigen detection in feces is 90%, and in serum is 65% in the acute setting. 3 , 4 Detection of Entamoeba antibodies in serum is possible in 70–90% of individuals within 5–7 days of acute infection; however, this is not helpful in differentiating acute from previous infections. 3 , 4 , 5 Finally, colonic biopsy specimens are not considered a routine diagnostic tool, and visualization of amoeba is rare. Nonspecific histopathological findings such as hemorrhagic regions of the colon, flask‐shaped ulcerations, necrosis of intestinal wall, and focal perforation may be associated with amoebic colitis, and the diagnostic yield may be increased with specialized stains such as the periodic acid‐Schiff stain. 4
Despite these tools, diagnosis of amoebic colitis remains challenging. This is highlighted in Case 3, where serology and serial fecal cultures were negative, possibly as a result of a prior course of metronidazole. In two cases, diagnosis was made on bowel histology, which is not common, and only one case was diagnosed by noninvasive means. Other published series have documented the diagnostic challenges associated with amoebic colitis; however, the majority are from developing countries where the incidence is higher. Gupta et al. demonstrated a fatal case of amoebic colitis in India, in which a patient was misdiagnosed and treated for IBD before developing fulminant necrotizing amoebic colitis, leading to multiorgan failure and death. 7 Cases 2 and 3 in our cohort also demonstrate the dangers of delayed diagnosis as these patients required emergency laparotomy following colonic perforation. Den et al. also reported the difficulties of diagnosing amoebic colitis whereby repeated colonic biopsies and stool cultures were negative for E. histolytica; diagnosis was ultimately confirmed serologically with resolution of symptoms following appropriate antimicrobial therapy. 8 Finally, Tufail et al. described a case series of amoebic colitis in the United Kingdom masquerading as IBD. 9 Guidelines were suggested by the authors to screen for E. histolytica in all patients presenting with colitis, with amoebic antimicrobial cover to be empirically commenced in patients receiving immunosuppression until results are available. 9
The Australian Therapeutic Guidelines recommend treatment of acute amoebic colitis (dysentery) using metronidazole 600 mg orally every eight hours for seven days. 10 However, if severe (i.e. blood in the stools, perforation, peritonitis), then escalated doses of metronidazole of either 750 mg intravenously or 800 mg orally every eight hours for seven days are required. 10 Once treatment is completed, an intraluminal cyst eradication agent, paromomycin 500 mg orally, every eight hours for seven days, should be used. 10 Paromomycin prevents relapse given that treatment failure may occur in up to 40–60% of patients treated with metronidazole alone. 4
In conclusion, this case series highlights the challenges in diagnosing amoebic colitis and the potentially life‐threatening consequences of misdiagnosis, inappropriate immunosuppression, and delayed antimicrobial therapy.
Acknowledgements
We acknowledge David Hugo Romero for his contributions to the graphic design. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33732890 | 18,712,261 | 2021-03 |
What was the outcome of reaction 'Large intestine perforation'? | Amoebic colitis: A case series of a recurring missed diagnosis.
Entamoeba histolytica, a pathogenic protozoan that causes amoebiasis, remains the second leading cause of death from parasitic infections worldwide. We present a case series of patients presenting to metropolitan tertiary gastroenterology units in Melbourne, Australia, highlighting the complexities of diagnosing amoebic colitis and the potential for misdiagnosis. These cases illustrate four key lessons in the identification of amoebic colitis: (i) obtaining a thorough travel and exposure history, (ii) having a high index of suspicion, (iii) understanding the limitations of available investigations, and (iv) being aware that amoebic colitis may masquerade as other common conditions.
Introduction
Entamoeba histolytica (E. histolytica) is the pathogenic protozoan responsible for amoebic colitis, a common parasitic infection, 1 and the second leading cause of death from parasitic infections worldwide. 2 The clinical presentation of amoebic colitis is varied and may include cramping abdominal pain, watery and/or bloody diarrhea, weight loss, fever, and anemia. Complications such as toxic megacolon, perianal ulceration, and colonic perforation are described, 3 and extraintestinal complications may arise secondary to hematogenous spread to sites such as the liver, brain, and lungs. 3
We present a case series of four patients diagnosed with amoebic colitis. These cases highlight the importance of obtaining a thorough travel and exposure history, maintaining a high index of suspicion, and understanding the limitations of available investigations in order to differentiate amoebiasis from common differential diagnoses such as inflammatory bowel disease (IBD), bacterial colitis, and colorectal cancer. 3
Case series presentations
Case 1
A 36‐year‐old Indian woman with a medical history significant for thalassemia minor was diagnosed with ulcerative proctitis in India in May 2019. She was treated with sulfasalazine and corticosteroids. A flare of ulcerative colitis (UC) was documented following medication noncompliance, which settled with oral metronidazole prescribed by a local general practitioner. Following travel to Australia, her symptoms recurred and persisted for several months until she presented to hospital with bloody diarrhea, nausea, vomiting, and loss of weight; she was also noted to be 24 weeks' pregnant. Treatment with rectal and oral 5‐aminosalicylic acid and oral prednisolone was commenced with an initial improvement in symptoms. Given her pregnancy status and improvement with medical management, endoscopy was not performed. She subsequently re‐presented with severe bloody diarrhea associated with tachycardia, anemia (hemoglobin 76 g/L), and leukocytosis. Intravenous corticosteroids were commenced, and a sigmoidoscopy demonstrated Mayo 3 proctitis (Fig. 1a). Fecal microscopy and tissue histology both demonstrated E. histolytica organisms, consistent with amoebic colitis. Intravenous metronidazole (750 mg three times a day) and metronidazole suppositories were commenced with rapid resolution of rectal bleeding. She was discharged with a seven‐day course of oral metronidazole (400 mg three times a day) followed by paromomycin (500 mg three times a day). She remained well and delivered a healthy child at term.
Figure 1 (a) Severe proctitis in the rectum. (b) CT angiography (portal‐venous phase) demonstrating hypodense lesions scattered throughout the liver. (c) Inflammation and ulceration of the colon. (d) Histology of the sigmoid colon demonstrating Entamoeba histolytica organisms with ingested red cells (arrows). Credit: David Hugo Romero.
Case 2
A 75‐year‐old previously well man, on holiday from India, presented to hospital with a two‐week history of abdominal pain, fever, watery, nonbloody diarrhea and anorexia. On examination, he was tachycardic (heart rate 115 beats per minute), tachypneic (respiratory rate 28 breaths/min), and febrile (38.1°C). Abdominal examination revealed a soft abdomen with right iliac fossa tenderness. Initial laboratory findings demonstrated an elevated white cell count (39.2 × 109/L) and C‐reactive protein (CRP) (379 mg/L). A CT abdomen revealed a phlegmonous mass adjacent to the caecum, raising the possibility of appendicitis along with multiple ill‐defined hepatic lesions.
The patient underwent a laparotomy where a perforated caecal mass with peritonitis was found. Intraoperative colonoscopy demonstrated ulceration of the rectum and transverse colon, and a subtotal‐colectomy with end‐ileostomy was performed. Postoperatively, worsening transaminitis was noted, and a CT liver demonstrated innumerable hypodense hepatic lesions consistent with liver abscesses (Fig. 1b), which were subsequently biopsied. Human immunodeficiency virus (HIV), amoebic, and Echinococcus serology and Mycobacterial microscopy and culture were all negative.
Histology of the resected bowel demonstrated numerous E. histolytica organisms with ulceration and caecal perforation; cultures from other sites were negative for amoebiasis. The patient required serial drainage of hepatic abscesses and ultimately recovered following intravenous metronidazole and prolonged oral paromomycin.
Case 3
A 45‐year‐old healthy man presented with four weeks of worsening nonbloody diarrhea, 11 kg of weight loss, and a perianal abscess with a communicating anal fistula. Prior to admission, his general practitioner had treated him for suspected food poisoning and commenced oral metronidazole following a positive stool culture for Blastocystis hominis. The patient denied recent travel or receptive anal intercourse. In hospital, a fistulotomy was performed, and intravenous hydrocortisone and antibiotics were commenced for ongoing diarrhea. A sigmoidoscopy demonstrated an anal fistula and deep ulceration with rectal sparing. A presumptive diagnosis of Crohn's disease was made. Subsequent magnetic resonance enterography showed no small bowel involvement. The patient was transferred to a tertiary center following large‐volume rectal bleeding.
On arrival, the patient was anemic (hemoglobin 70 g/L) with an elevated CRP of 172 mg/L. Three fecal specimens were obtained and tested, and ova‐cyst‐parasite (OCP) analysis and amoebiasis, schistosomiasis, strongyloides, and syphilis serology were negative. A colonoscopy revealed moderate ileitis and multiple pancolonic serpiginous ulcers (Fig. 1c), further supporting a diagnosis of atypical ileocolonic and perianal Crohn's disease, and infliximab 10 mg/kg was commenced. Three days later, the patient deteriorated with fever and left iliac fossa pain. A CT abdomen demonstrated spontaneous sigmoid colon perforation with intraperitoneal free gas. He underwent an emergency laparotomy and Hartmann's procedure; histopathology demonstrated acute colitis and copious E. histolytica organisms (Fig. 1d). Intravenous metronidazole (750 mg tds) was commenced, and the patient made a full recovery.
Case 4
A 24‐year‐old Indian woman presented to hospital with a 10‐day history of abdominal pain, weight loss, and severe bloody diarrhea on a background of known UC. Her UC was diagnosed in India in 2018 and managed with mesalazine monotherapy.
On examination, vital signs were within normal limits, and abdominal examination revealed right‐sided involuntary guarding and tenderness. The patient was anemic (hemoglobin 93 g/L) with normal inflammatory markers. A CT abdomen showed rectal mucosal hyperenhancement. Intravenous hydrocortisone was commenced for a suspected UC flare, and a flexible sigmoidoscopy demonstrated Mayo 2 proctitis. HIV, hepatitis, and mycobacterium serology were negative. Stool microscopy was positive for E. histolytica organisms. Oral metronidazole followed by paromomycin were commenced, corticosteroids were weaned, and mesalazine was ceased. Bowel histology did not demonstrate amoebiasis.
Discussion
These cases highlight the challenges and pitfalls of diagnosing amoebic colitis in developed countries where the incidence is low. Significant variation in presenting symptoms, previous misdiagnosis, and amoebiasis masquerading as other common conditions all contribute to missed or late diagnoses, which can result in development of life‐threatening complications. In addition, these cases highlight the importance of a comprehensive travel history and maintaining an index of suspicion, even in patients with diagnosed IBD. We recommend that clinicians consider invasive amoebiasis in their list of differentials and be aware that it is both a local and imported disease. 1
E. histolytica infection begins with ingestion of cysts, typically through fecally contaminated water or food. In the small bowel, excystation occurs with the formation of mobile and invasive trophozoites, which aggregate in the mucin layer of the intestines, forming cysts and destroying colonic epithelium. 3 Approximately 90% of cases are self‐limiting and asymptomatic, 4 with spontaneous clearance of infection. 1 Symptoms of abdominal pain, watery and/or bloody diarrhea, weight loss, and fevers occur in 10% cases, and extraintestinal spread is noted in <1%. 4
E. histolytica is endemic to India, Southeast Asia, Egypt, and Mexico. 1 , 2 van Hal et al. reported that invasive amoebiasis has been prevalent in northern Australia, leading to locally acquired cases. 1 High‐risk populations in Australia include indigenous Australians, immigrants, residents returning from endemic countries, and men who have sex with men. 1 In this series, three of four patients had recently traveled to India; however, one case acquired E. histolytica despite no domestic or international travel. This has not previously been reported and illustrates the potential for local transmission.
Diagnostic tools for intestinal amoebiasis include: fecal microscopy, fecal polymerase chain reaction (PCR), fecal and/or serum antigen detection, serology, and histologic examination of colonic biopsy specimens. 5 Fecal microscopy is the most common first‐line investigation, particularly in developing countries; however, the sensitivity to identify cysts and/or trophozoites is suboptimal at 25–60%. 4 Given that organism excretion can vary, three specimens taken on separate days are recommended to increase the diagnostic yield. 5 Fecal PCR has a sensitivity >70% and a specificity >90%. 6 The sensitivity of antigen detection in feces is 90%, and in serum is 65% in the acute setting. 3 , 4 Detection of Entamoeba antibodies in serum is possible in 70–90% of individuals within 5–7 days of acute infection; however, this is not helpful in differentiating acute from previous infections. 3 , 4 , 5 Finally, colonic biopsy specimens are not considered a routine diagnostic tool, and visualization of amoeba is rare. Nonspecific histopathological findings such as hemorrhagic regions of the colon, flask‐shaped ulcerations, necrosis of intestinal wall, and focal perforation may be associated with amoebic colitis, and the diagnostic yield may be increased with specialized stains such as the periodic acid‐Schiff stain. 4
Despite these tools, diagnosis of amoebic colitis remains challenging. This is highlighted in Case 3, where serology and serial fecal cultures were negative, possibly as a result of a prior course of metronidazole. In two cases, diagnosis was made on bowel histology, which is not common, and only one case was diagnosed by noninvasive means. Other published series have documented the diagnostic challenges associated with amoebic colitis; however, the majority are from developing countries where the incidence is higher. Gupta et al. demonstrated a fatal case of amoebic colitis in India, in which a patient was misdiagnosed and treated for IBD before developing fulminant necrotizing amoebic colitis, leading to multiorgan failure and death. 7 Cases 2 and 3 in our cohort also demonstrate the dangers of delayed diagnosis as these patients required emergency laparotomy following colonic perforation. Den et al. also reported the difficulties of diagnosing amoebic colitis whereby repeated colonic biopsies and stool cultures were negative for E. histolytica; diagnosis was ultimately confirmed serologically with resolution of symptoms following appropriate antimicrobial therapy. 8 Finally, Tufail et al. described a case series of amoebic colitis in the United Kingdom masquerading as IBD. 9 Guidelines were suggested by the authors to screen for E. histolytica in all patients presenting with colitis, with amoebic antimicrobial cover to be empirically commenced in patients receiving immunosuppression until results are available. 9
The Australian Therapeutic Guidelines recommend treatment of acute amoebic colitis (dysentery) using metronidazole 600 mg orally every eight hours for seven days. 10 However, if severe (i.e. blood in the stools, perforation, peritonitis), then escalated doses of metronidazole of either 750 mg intravenously or 800 mg orally every eight hours for seven days are required. 10 Once treatment is completed, an intraluminal cyst eradication agent, paromomycin 500 mg orally, every eight hours for seven days, should be used. 10 Paromomycin prevents relapse given that treatment failure may occur in up to 40–60% of patients treated with metronidazole alone. 4
In conclusion, this case series highlights the challenges in diagnosing amoebic colitis and the potentially life‐threatening consequences of misdiagnosis, inappropriate immunosuppression, and delayed antimicrobial therapy.
Acknowledgements
We acknowledge David Hugo Romero for his contributions to the graphic design. | Recovered | ReactionOutcome | CC BY-NC-ND | 33732890 | 18,712,261 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Conjunctival oedema'. | Massive spontaneous subconjunctival hemorrhage in a patient on therapeutic warfarin: A case report.
To describe a case of massive spontaneous subconjunctival hemorrhage in a patient taking warfarin with a therapeutic international normalized ratio (INR).
Massive circumferential hemorrhagic chemosis, extensive periorbital and facial ecchymosis, and active arterial extravasation in the subconjunctiva which required cessation and reversal of anticoagulation. Findings gradually resolved over several months after discharge.
While subconjunctival hemorrhage, even in anticoagulated patients, is usually benign, rare examples of severe presentations exist. We present, to our knowledge, the first documented case of a subconjunctival hemorrhage necessitating cessation and reversal of anticoagulation in the setting of a therapeutic INR.
1 Introduction
Subconjunctival hemorrhage (SCH) is a typically benign process characterized by acute, painless bleeding into the subconjunctival space.1 It is a common ocular condition with risk factors that include hypertension, hyperlipidemia, diabetes mellitus, anticoagulation therapy, and increased age (particularly over 50-years old given the previously mentioned risk factors).2 While often spontaneous, SCH can be caused by Valsalva maneuvers, ocular and orbital trauma, and potentially serious systemic causes of coagulopathy.3 Warfarin, the most prescribed outpatient anticoagulant in North America, is a known cause of spontaneous SCH, with an incidence of 0.35–1.56%.4,5
While a supratherapeutic international normalized ratio (INR) has not been shown to increase the risk of SCH, patients on warfarin with SCH should have their INR and prothrombin time (PT) checked to evaluate systemic coagulation status.1,5 Warfarin-associated SCH usually resolves spontaneously after 5–10 days and rarely requires more than supportive care.5 Documented cases of severe warfarin-associated SCH requiring cessation of anticoagulation,6 cessation and surgical evacuation,7 or cessation and reversal of supratherapeutic anticoagulation are extremely rare in the literature.8 Usually, SCH are self-limiting, not overly severe, and do not require intervention. Therefore, formalized guidelines for proper anticoagulation management in warfarin-associated SCH do not exist and clinical judgement usually dictates treatment strategy.
Herein, we present a case that, to our knowledge, is the only reported occurrence of a warfarin-associated SCH in which the severity of presentation necessitated inpatient admission with cessation and reversal of anticoagulation in the setting of a therapeutic INR. This uniquely severe presentation of a condition universally regarded as benign provides the opportunity to examine the current literature regarding warfarin-associated SCH and offer insights to management strategies.
2 Case report
An 86-year-old Caucasian male presented to our institution's Emergency Department (ED) in May 2020 with progressive swelling and bleeding of his right eye with visual obstruction. His medical history was significant for hypertension, grade III chronic kidney disease, and atrial fibrillation. His ocular history was significant for bilateral cataract extractions with PCIOL implantation in 2013 and bilateral YAG laser capsulotomies in 2013. His medications were significant for Aspirin-CaCO3 81–300 mg daily, metoprolol ER 50 mg daily, and warfarin 2.5 mg daily with two days of 3.75 mg dosing. The rest of his history was non-contributory.
One week prior to presentation, the patient noticed an initially small, but slowly progressive, amount of blood overlying the sclera of his right eye. He eventually experienced slight obstruction of his vision from the blood as well as minor periorbital ecchymosis. Two days prior to presentation, the patient was diagnosed with a small SCH by an outside ophthalmologist and was instructed to discontinue his warfarin and was told to not worry about the bleeding. After two days of progressive bleeding, he presented to an outside hospital ED, where active subconjunctival bleeding and hemorrhagic chemosis were documented. Laboratory evaluation at that time showed an INR of 2.85 with a PT of 32.9. Due to this atypical presentation, the patient was referred to our institution for further management.
On presentation to our ED, the patient denied any pain, dizziness, blurry vision, or history of recent trauma to the eye or face. Of note, the patient was normotensive with a blood pressure of 120/81 mmHg. Best visual acuity sans correction was found to be 20/80 in the right eye and 20/40 in the left eye. Intraocular pressure and pupillary exam were both within normal limits. External examination revealed periorbital ecchymosis with trace edema, massive 360-degree hemorrhagic chemosis, and active bleeding from the subconjunctiva with overflow onto the patient's face (Fig. 1A, Fig. 1BA, B). Extraocular movements in the right eye were restricted 50% in all quadrants, while there were no restrictions in the left eye. Slit lamp and fundus examinations revealed no further abnormalities.Fig. 1A Right eye, upper lid manually retracted superiorly. Active extravasation and massive hemorrhagic chemosis can be seen, with blood overflowing the lower lid and draining down the patient's face.
Fig. 1A
Fig. 1B Extensive periorbital ecchymosis can be appreciated with inferior extension to the right jaw.
Fig. 1B
Laboratory workup was significant for an INR of 2.7 (normal range of 0.9–1.1, and 2.0–3.0 with therapeutic anticoagulation), a PT of 32.9 s (normal range of 12.1–15.1 s), and an initial hemoglobin of 14.3 g/dL which decreased to 13.6 g/dL 4 h later. Due to the active nature of the bleeding, a CT-Angiogram of the head with/without contrast was ordered, which revealed a small preseptal hematoma anterior to the right globe with a focus of active arterial extravasation of unclear source. No vascular malformations or large lacerations corresponding to the area of bleeding were noted. After discussion with the patient's internal medicine team, the decision was made to reverse the warfarin with 2.5 mg of Vitamin K and 1 unit of fresh frozen plasma. At this point, copious erythromycin ointment and pressure patches were applied to the right eye.
Several hours after admission the source of bleeding was identified as a small artery in the superficial inferonasal bulbar conjunctiva near the medial canthus and finally controlled with application of focal pressure patches for 25 and then 15 minutes. No additional management was necessary for several hours until the patient snorted and began actively bleeding again. Focal pressure patches were again applied to the source, twice for 30 minutes each, with subsequent hemostasis. Although surgical management and cautery were discussed with the patient, due to the recurrent severe bleeding, the patient was hesitant to pursue surgical measures and ultimately elected to continue patching upon further bleeding.
Regular ophthalmic examinations continued for two more days, with no further bleeding or ophthalmic complications, at which point the patient was cleared by Ophthalmology for discharge. The patient was medically managed for several more days due to episodes of atrial fibrillation and was discharged from the hospital five days after admission. At his final follow-up appointment, 3 months post-discharge, the patient had no recurrence of bleeding or other related complications, except for a mild contact dermatitis from the initial choice of antibiotic ointment. The patient's SCH and periorbital ecchymosis completely resolved over the course of follow-up and corrected vision in the right eye improved to baseline acuity of 20/40.
3 Discussion
This case demonstrates an atypically massive spontaneous SCH in a patient on therapeutic warfarin. With no reported trauma, previous occurrence of similar bleeds, or known lesions near the site of the bleed, this presentation is disproportionately severe and markedly inconsistent in magnitude compared to the expectedly small SCH in patients taking warfarin.4, 5, 6 While the exact cause of this patient's bleed may never be fully known, it is possible that the small bulbar vessel was initially damaged by a strong Valsalva maneuver since the patient denied any obvious trauma or eye rubbing. While the difference between therapeutic and supratherapeutic INR has not been shown to increase the risk of SCH in patients taking warfarin,1,5 the impressive amount of hemorrhage was certainly more suggestive of a further hypocoagulable state than the therapeutic INR found on laboratory examination. The only other documented case of warfarin cessation and reversal due solely to an SCH was in a patient with a supratherapeutic INR, further highlighting the distinctiveness of this presentation.8
Due to the lack of formal guidelines on managing an SCH of such atypical severity, clinical judgement was the sole determinant of management course. Discontinuation and reversal of warfarin was deemed necessary in this case due to the severity of the bleeding and mass effect on surrounding tissues. Had the bleeding not been so robust as to threaten the patient's vision, it may have been possible to manage the bleeding while maintaining anticoagulation. Once the bleeding vessel was identified, cautery versus surgical repair of the vessel was strongly considered due to the quantity of hemorrhage and fear of further recurrence leading to blood loss or visual impairment. However, due to the patient's choice for non-surgical management, conservative therapy with focal tamponade was further trialed with clear success as described. While the viability of anticoagulation reversal and conservative management of such a severe SCH is supported by this particular case report, it should be recognized as preliminary at this time. It may serve as an initial data point for future practitioners when faced with an SCH of this magnitude in an anticoagulated patient.
4 Conclusions
This case report highlights that, while extremely rare, spontaneous SCH in patients anticoagulated with warfarin may present with severity requiring focal tamponade, cessation and/or reversal of anticoagulation, or surgical management. To our knowledge, this is the first report to describe a warfarin-associated SCH of sufficient severity to require cessation and reversal of anticoagulation in a patient with a therapeutic INR. This report may also serve as a cautionary tale that even the most apparently benign condition, such as a SCH, can have atypical and severe presentations, and as such should not be dismissed without thorough examination or workup.
Patient consent
The patient provided both verbal and written consent for the use of his medical history and images to be written and submitted as a case report.
Funding
No funding or grant support.
Authorship
All authors attest that they meet the current ICMJE criteria.
Declaration of competing interest
None. | ASPIRIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33732947 | 19,443,961 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Labelled drug-drug interaction medication error'. | Massive spontaneous subconjunctival hemorrhage in a patient on therapeutic warfarin: A case report.
To describe a case of massive spontaneous subconjunctival hemorrhage in a patient taking warfarin with a therapeutic international normalized ratio (INR).
Massive circumferential hemorrhagic chemosis, extensive periorbital and facial ecchymosis, and active arterial extravasation in the subconjunctiva which required cessation and reversal of anticoagulation. Findings gradually resolved over several months after discharge.
While subconjunctival hemorrhage, even in anticoagulated patients, is usually benign, rare examples of severe presentations exist. We present, to our knowledge, the first documented case of a subconjunctival hemorrhage necessitating cessation and reversal of anticoagulation in the setting of a therapeutic INR.
1 Introduction
Subconjunctival hemorrhage (SCH) is a typically benign process characterized by acute, painless bleeding into the subconjunctival space.1 It is a common ocular condition with risk factors that include hypertension, hyperlipidemia, diabetes mellitus, anticoagulation therapy, and increased age (particularly over 50-years old given the previously mentioned risk factors).2 While often spontaneous, SCH can be caused by Valsalva maneuvers, ocular and orbital trauma, and potentially serious systemic causes of coagulopathy.3 Warfarin, the most prescribed outpatient anticoagulant in North America, is a known cause of spontaneous SCH, with an incidence of 0.35–1.56%.4,5
While a supratherapeutic international normalized ratio (INR) has not been shown to increase the risk of SCH, patients on warfarin with SCH should have their INR and prothrombin time (PT) checked to evaluate systemic coagulation status.1,5 Warfarin-associated SCH usually resolves spontaneously after 5–10 days and rarely requires more than supportive care.5 Documented cases of severe warfarin-associated SCH requiring cessation of anticoagulation,6 cessation and surgical evacuation,7 or cessation and reversal of supratherapeutic anticoagulation are extremely rare in the literature.8 Usually, SCH are self-limiting, not overly severe, and do not require intervention. Therefore, formalized guidelines for proper anticoagulation management in warfarin-associated SCH do not exist and clinical judgement usually dictates treatment strategy.
Herein, we present a case that, to our knowledge, is the only reported occurrence of a warfarin-associated SCH in which the severity of presentation necessitated inpatient admission with cessation and reversal of anticoagulation in the setting of a therapeutic INR. This uniquely severe presentation of a condition universally regarded as benign provides the opportunity to examine the current literature regarding warfarin-associated SCH and offer insights to management strategies.
2 Case report
An 86-year-old Caucasian male presented to our institution's Emergency Department (ED) in May 2020 with progressive swelling and bleeding of his right eye with visual obstruction. His medical history was significant for hypertension, grade III chronic kidney disease, and atrial fibrillation. His ocular history was significant for bilateral cataract extractions with PCIOL implantation in 2013 and bilateral YAG laser capsulotomies in 2013. His medications were significant for Aspirin-CaCO3 81–300 mg daily, metoprolol ER 50 mg daily, and warfarin 2.5 mg daily with two days of 3.75 mg dosing. The rest of his history was non-contributory.
One week prior to presentation, the patient noticed an initially small, but slowly progressive, amount of blood overlying the sclera of his right eye. He eventually experienced slight obstruction of his vision from the blood as well as minor periorbital ecchymosis. Two days prior to presentation, the patient was diagnosed with a small SCH by an outside ophthalmologist and was instructed to discontinue his warfarin and was told to not worry about the bleeding. After two days of progressive bleeding, he presented to an outside hospital ED, where active subconjunctival bleeding and hemorrhagic chemosis were documented. Laboratory evaluation at that time showed an INR of 2.85 with a PT of 32.9. Due to this atypical presentation, the patient was referred to our institution for further management.
On presentation to our ED, the patient denied any pain, dizziness, blurry vision, or history of recent trauma to the eye or face. Of note, the patient was normotensive with a blood pressure of 120/81 mmHg. Best visual acuity sans correction was found to be 20/80 in the right eye and 20/40 in the left eye. Intraocular pressure and pupillary exam were both within normal limits. External examination revealed periorbital ecchymosis with trace edema, massive 360-degree hemorrhagic chemosis, and active bleeding from the subconjunctiva with overflow onto the patient's face (Fig. 1A, Fig. 1BA, B). Extraocular movements in the right eye were restricted 50% in all quadrants, while there were no restrictions in the left eye. Slit lamp and fundus examinations revealed no further abnormalities.Fig. 1A Right eye, upper lid manually retracted superiorly. Active extravasation and massive hemorrhagic chemosis can be seen, with blood overflowing the lower lid and draining down the patient's face.
Fig. 1A
Fig. 1B Extensive periorbital ecchymosis can be appreciated with inferior extension to the right jaw.
Fig. 1B
Laboratory workup was significant for an INR of 2.7 (normal range of 0.9–1.1, and 2.0–3.0 with therapeutic anticoagulation), a PT of 32.9 s (normal range of 12.1–15.1 s), and an initial hemoglobin of 14.3 g/dL which decreased to 13.6 g/dL 4 h later. Due to the active nature of the bleeding, a CT-Angiogram of the head with/without contrast was ordered, which revealed a small preseptal hematoma anterior to the right globe with a focus of active arterial extravasation of unclear source. No vascular malformations or large lacerations corresponding to the area of bleeding were noted. After discussion with the patient's internal medicine team, the decision was made to reverse the warfarin with 2.5 mg of Vitamin K and 1 unit of fresh frozen plasma. At this point, copious erythromycin ointment and pressure patches were applied to the right eye.
Several hours after admission the source of bleeding was identified as a small artery in the superficial inferonasal bulbar conjunctiva near the medial canthus and finally controlled with application of focal pressure patches for 25 and then 15 minutes. No additional management was necessary for several hours until the patient snorted and began actively bleeding again. Focal pressure patches were again applied to the source, twice for 30 minutes each, with subsequent hemostasis. Although surgical management and cautery were discussed with the patient, due to the recurrent severe bleeding, the patient was hesitant to pursue surgical measures and ultimately elected to continue patching upon further bleeding.
Regular ophthalmic examinations continued for two more days, with no further bleeding or ophthalmic complications, at which point the patient was cleared by Ophthalmology for discharge. The patient was medically managed for several more days due to episodes of atrial fibrillation and was discharged from the hospital five days after admission. At his final follow-up appointment, 3 months post-discharge, the patient had no recurrence of bleeding or other related complications, except for a mild contact dermatitis from the initial choice of antibiotic ointment. The patient's SCH and periorbital ecchymosis completely resolved over the course of follow-up and corrected vision in the right eye improved to baseline acuity of 20/40.
3 Discussion
This case demonstrates an atypically massive spontaneous SCH in a patient on therapeutic warfarin. With no reported trauma, previous occurrence of similar bleeds, or known lesions near the site of the bleed, this presentation is disproportionately severe and markedly inconsistent in magnitude compared to the expectedly small SCH in patients taking warfarin.4, 5, 6 While the exact cause of this patient's bleed may never be fully known, it is possible that the small bulbar vessel was initially damaged by a strong Valsalva maneuver since the patient denied any obvious trauma or eye rubbing. While the difference between therapeutic and supratherapeutic INR has not been shown to increase the risk of SCH in patients taking warfarin,1,5 the impressive amount of hemorrhage was certainly more suggestive of a further hypocoagulable state than the therapeutic INR found on laboratory examination. The only other documented case of warfarin cessation and reversal due solely to an SCH was in a patient with a supratherapeutic INR, further highlighting the distinctiveness of this presentation.8
Due to the lack of formal guidelines on managing an SCH of such atypical severity, clinical judgement was the sole determinant of management course. Discontinuation and reversal of warfarin was deemed necessary in this case due to the severity of the bleeding and mass effect on surrounding tissues. Had the bleeding not been so robust as to threaten the patient's vision, it may have been possible to manage the bleeding while maintaining anticoagulation. Once the bleeding vessel was identified, cautery versus surgical repair of the vessel was strongly considered due to the quantity of hemorrhage and fear of further recurrence leading to blood loss or visual impairment. However, due to the patient's choice for non-surgical management, conservative therapy with focal tamponade was further trialed with clear success as described. While the viability of anticoagulation reversal and conservative management of such a severe SCH is supported by this particular case report, it should be recognized as preliminary at this time. It may serve as an initial data point for future practitioners when faced with an SCH of this magnitude in an anticoagulated patient.
4 Conclusions
This case report highlights that, while extremely rare, spontaneous SCH in patients anticoagulated with warfarin may present with severity requiring focal tamponade, cessation and/or reversal of anticoagulation, or surgical management. To our knowledge, this is the first report to describe a warfarin-associated SCH of sufficient severity to require cessation and reversal of anticoagulation in a patient with a therapeutic INR. This report may also serve as a cautionary tale that even the most apparently benign condition, such as a SCH, can have atypical and severe presentations, and as such should not be dismissed without thorough examination or workup.
Patient consent
The patient provided both verbal and written consent for the use of his medical history and images to be written and submitted as a case report.
Funding
No funding or grant support.
Authorship
All authors attest that they meet the current ICMJE criteria.
Declaration of competing interest
None. | ASPIRIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33732947 | 19,443,961 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Periorbital haematoma'. | Massive spontaneous subconjunctival hemorrhage in a patient on therapeutic warfarin: A case report.
To describe a case of massive spontaneous subconjunctival hemorrhage in a patient taking warfarin with a therapeutic international normalized ratio (INR).
Massive circumferential hemorrhagic chemosis, extensive periorbital and facial ecchymosis, and active arterial extravasation in the subconjunctiva which required cessation and reversal of anticoagulation. Findings gradually resolved over several months after discharge.
While subconjunctival hemorrhage, even in anticoagulated patients, is usually benign, rare examples of severe presentations exist. We present, to our knowledge, the first documented case of a subconjunctival hemorrhage necessitating cessation and reversal of anticoagulation in the setting of a therapeutic INR.
1 Introduction
Subconjunctival hemorrhage (SCH) is a typically benign process characterized by acute, painless bleeding into the subconjunctival space.1 It is a common ocular condition with risk factors that include hypertension, hyperlipidemia, diabetes mellitus, anticoagulation therapy, and increased age (particularly over 50-years old given the previously mentioned risk factors).2 While often spontaneous, SCH can be caused by Valsalva maneuvers, ocular and orbital trauma, and potentially serious systemic causes of coagulopathy.3 Warfarin, the most prescribed outpatient anticoagulant in North America, is a known cause of spontaneous SCH, with an incidence of 0.35–1.56%.4,5
While a supratherapeutic international normalized ratio (INR) has not been shown to increase the risk of SCH, patients on warfarin with SCH should have their INR and prothrombin time (PT) checked to evaluate systemic coagulation status.1,5 Warfarin-associated SCH usually resolves spontaneously after 5–10 days and rarely requires more than supportive care.5 Documented cases of severe warfarin-associated SCH requiring cessation of anticoagulation,6 cessation and surgical evacuation,7 or cessation and reversal of supratherapeutic anticoagulation are extremely rare in the literature.8 Usually, SCH are self-limiting, not overly severe, and do not require intervention. Therefore, formalized guidelines for proper anticoagulation management in warfarin-associated SCH do not exist and clinical judgement usually dictates treatment strategy.
Herein, we present a case that, to our knowledge, is the only reported occurrence of a warfarin-associated SCH in which the severity of presentation necessitated inpatient admission with cessation and reversal of anticoagulation in the setting of a therapeutic INR. This uniquely severe presentation of a condition universally regarded as benign provides the opportunity to examine the current literature regarding warfarin-associated SCH and offer insights to management strategies.
2 Case report
An 86-year-old Caucasian male presented to our institution's Emergency Department (ED) in May 2020 with progressive swelling and bleeding of his right eye with visual obstruction. His medical history was significant for hypertension, grade III chronic kidney disease, and atrial fibrillation. His ocular history was significant for bilateral cataract extractions with PCIOL implantation in 2013 and bilateral YAG laser capsulotomies in 2013. His medications were significant for Aspirin-CaCO3 81–300 mg daily, metoprolol ER 50 mg daily, and warfarin 2.5 mg daily with two days of 3.75 mg dosing. The rest of his history was non-contributory.
One week prior to presentation, the patient noticed an initially small, but slowly progressive, amount of blood overlying the sclera of his right eye. He eventually experienced slight obstruction of his vision from the blood as well as minor periorbital ecchymosis. Two days prior to presentation, the patient was diagnosed with a small SCH by an outside ophthalmologist and was instructed to discontinue his warfarin and was told to not worry about the bleeding. After two days of progressive bleeding, he presented to an outside hospital ED, where active subconjunctival bleeding and hemorrhagic chemosis were documented. Laboratory evaluation at that time showed an INR of 2.85 with a PT of 32.9. Due to this atypical presentation, the patient was referred to our institution for further management.
On presentation to our ED, the patient denied any pain, dizziness, blurry vision, or history of recent trauma to the eye or face. Of note, the patient was normotensive with a blood pressure of 120/81 mmHg. Best visual acuity sans correction was found to be 20/80 in the right eye and 20/40 in the left eye. Intraocular pressure and pupillary exam were both within normal limits. External examination revealed periorbital ecchymosis with trace edema, massive 360-degree hemorrhagic chemosis, and active bleeding from the subconjunctiva with overflow onto the patient's face (Fig. 1A, Fig. 1BA, B). Extraocular movements in the right eye were restricted 50% in all quadrants, while there were no restrictions in the left eye. Slit lamp and fundus examinations revealed no further abnormalities.Fig. 1A Right eye, upper lid manually retracted superiorly. Active extravasation and massive hemorrhagic chemosis can be seen, with blood overflowing the lower lid and draining down the patient's face.
Fig. 1A
Fig. 1B Extensive periorbital ecchymosis can be appreciated with inferior extension to the right jaw.
Fig. 1B
Laboratory workup was significant for an INR of 2.7 (normal range of 0.9–1.1, and 2.0–3.0 with therapeutic anticoagulation), a PT of 32.9 s (normal range of 12.1–15.1 s), and an initial hemoglobin of 14.3 g/dL which decreased to 13.6 g/dL 4 h later. Due to the active nature of the bleeding, a CT-Angiogram of the head with/without contrast was ordered, which revealed a small preseptal hematoma anterior to the right globe with a focus of active arterial extravasation of unclear source. No vascular malformations or large lacerations corresponding to the area of bleeding were noted. After discussion with the patient's internal medicine team, the decision was made to reverse the warfarin with 2.5 mg of Vitamin K and 1 unit of fresh frozen plasma. At this point, copious erythromycin ointment and pressure patches were applied to the right eye.
Several hours after admission the source of bleeding was identified as a small artery in the superficial inferonasal bulbar conjunctiva near the medial canthus and finally controlled with application of focal pressure patches for 25 and then 15 minutes. No additional management was necessary for several hours until the patient snorted and began actively bleeding again. Focal pressure patches were again applied to the source, twice for 30 minutes each, with subsequent hemostasis. Although surgical management and cautery were discussed with the patient, due to the recurrent severe bleeding, the patient was hesitant to pursue surgical measures and ultimately elected to continue patching upon further bleeding.
Regular ophthalmic examinations continued for two more days, with no further bleeding or ophthalmic complications, at which point the patient was cleared by Ophthalmology for discharge. The patient was medically managed for several more days due to episodes of atrial fibrillation and was discharged from the hospital five days after admission. At his final follow-up appointment, 3 months post-discharge, the patient had no recurrence of bleeding or other related complications, except for a mild contact dermatitis from the initial choice of antibiotic ointment. The patient's SCH and periorbital ecchymosis completely resolved over the course of follow-up and corrected vision in the right eye improved to baseline acuity of 20/40.
3 Discussion
This case demonstrates an atypically massive spontaneous SCH in a patient on therapeutic warfarin. With no reported trauma, previous occurrence of similar bleeds, or known lesions near the site of the bleed, this presentation is disproportionately severe and markedly inconsistent in magnitude compared to the expectedly small SCH in patients taking warfarin.4, 5, 6 While the exact cause of this patient's bleed may never be fully known, it is possible that the small bulbar vessel was initially damaged by a strong Valsalva maneuver since the patient denied any obvious trauma or eye rubbing. While the difference between therapeutic and supratherapeutic INR has not been shown to increase the risk of SCH in patients taking warfarin,1,5 the impressive amount of hemorrhage was certainly more suggestive of a further hypocoagulable state than the therapeutic INR found on laboratory examination. The only other documented case of warfarin cessation and reversal due solely to an SCH was in a patient with a supratherapeutic INR, further highlighting the distinctiveness of this presentation.8
Due to the lack of formal guidelines on managing an SCH of such atypical severity, clinical judgement was the sole determinant of management course. Discontinuation and reversal of warfarin was deemed necessary in this case due to the severity of the bleeding and mass effect on surrounding tissues. Had the bleeding not been so robust as to threaten the patient's vision, it may have been possible to manage the bleeding while maintaining anticoagulation. Once the bleeding vessel was identified, cautery versus surgical repair of the vessel was strongly considered due to the quantity of hemorrhage and fear of further recurrence leading to blood loss or visual impairment. However, due to the patient's choice for non-surgical management, conservative therapy with focal tamponade was further trialed with clear success as described. While the viability of anticoagulation reversal and conservative management of such a severe SCH is supported by this particular case report, it should be recognized as preliminary at this time. It may serve as an initial data point for future practitioners when faced with an SCH of this magnitude in an anticoagulated patient.
4 Conclusions
This case report highlights that, while extremely rare, spontaneous SCH in patients anticoagulated with warfarin may present with severity requiring focal tamponade, cessation and/or reversal of anticoagulation, or surgical management. To our knowledge, this is the first report to describe a warfarin-associated SCH of sufficient severity to require cessation and reversal of anticoagulation in a patient with a therapeutic INR. This report may also serve as a cautionary tale that even the most apparently benign condition, such as a SCH, can have atypical and severe presentations, and as such should not be dismissed without thorough examination or workup.
Patient consent
The patient provided both verbal and written consent for the use of his medical history and images to be written and submitted as a case report.
Funding
No funding or grant support.
Authorship
All authors attest that they meet the current ICMJE criteria.
Declaration of competing interest
None. | ASPIRIN, WARFARIN | DrugsGivenReaction | CC BY-NC-ND | 33732947 | 19,443,961 | 2021-06 |
What was the dosage of drug 'WARFARIN SODIUM'? | Massive spontaneous subconjunctival hemorrhage in a patient on therapeutic warfarin: A case report.
To describe a case of massive spontaneous subconjunctival hemorrhage in a patient taking warfarin with a therapeutic international normalized ratio (INR).
Massive circumferential hemorrhagic chemosis, extensive periorbital and facial ecchymosis, and active arterial extravasation in the subconjunctiva which required cessation and reversal of anticoagulation. Findings gradually resolved over several months after discharge.
While subconjunctival hemorrhage, even in anticoagulated patients, is usually benign, rare examples of severe presentations exist. We present, to our knowledge, the first documented case of a subconjunctival hemorrhage necessitating cessation and reversal of anticoagulation in the setting of a therapeutic INR.
1 Introduction
Subconjunctival hemorrhage (SCH) is a typically benign process characterized by acute, painless bleeding into the subconjunctival space.1 It is a common ocular condition with risk factors that include hypertension, hyperlipidemia, diabetes mellitus, anticoagulation therapy, and increased age (particularly over 50-years old given the previously mentioned risk factors).2 While often spontaneous, SCH can be caused by Valsalva maneuvers, ocular and orbital trauma, and potentially serious systemic causes of coagulopathy.3 Warfarin, the most prescribed outpatient anticoagulant in North America, is a known cause of spontaneous SCH, with an incidence of 0.35–1.56%.4,5
While a supratherapeutic international normalized ratio (INR) has not been shown to increase the risk of SCH, patients on warfarin with SCH should have their INR and prothrombin time (PT) checked to evaluate systemic coagulation status.1,5 Warfarin-associated SCH usually resolves spontaneously after 5–10 days and rarely requires more than supportive care.5 Documented cases of severe warfarin-associated SCH requiring cessation of anticoagulation,6 cessation and surgical evacuation,7 or cessation and reversal of supratherapeutic anticoagulation are extremely rare in the literature.8 Usually, SCH are self-limiting, not overly severe, and do not require intervention. Therefore, formalized guidelines for proper anticoagulation management in warfarin-associated SCH do not exist and clinical judgement usually dictates treatment strategy.
Herein, we present a case that, to our knowledge, is the only reported occurrence of a warfarin-associated SCH in which the severity of presentation necessitated inpatient admission with cessation and reversal of anticoagulation in the setting of a therapeutic INR. This uniquely severe presentation of a condition universally regarded as benign provides the opportunity to examine the current literature regarding warfarin-associated SCH and offer insights to management strategies.
2 Case report
An 86-year-old Caucasian male presented to our institution's Emergency Department (ED) in May 2020 with progressive swelling and bleeding of his right eye with visual obstruction. His medical history was significant for hypertension, grade III chronic kidney disease, and atrial fibrillation. His ocular history was significant for bilateral cataract extractions with PCIOL implantation in 2013 and bilateral YAG laser capsulotomies in 2013. His medications were significant for Aspirin-CaCO3 81–300 mg daily, metoprolol ER 50 mg daily, and warfarin 2.5 mg daily with two days of 3.75 mg dosing. The rest of his history was non-contributory.
One week prior to presentation, the patient noticed an initially small, but slowly progressive, amount of blood overlying the sclera of his right eye. He eventually experienced slight obstruction of his vision from the blood as well as minor periorbital ecchymosis. Two days prior to presentation, the patient was diagnosed with a small SCH by an outside ophthalmologist and was instructed to discontinue his warfarin and was told to not worry about the bleeding. After two days of progressive bleeding, he presented to an outside hospital ED, where active subconjunctival bleeding and hemorrhagic chemosis were documented. Laboratory evaluation at that time showed an INR of 2.85 with a PT of 32.9. Due to this atypical presentation, the patient was referred to our institution for further management.
On presentation to our ED, the patient denied any pain, dizziness, blurry vision, or history of recent trauma to the eye or face. Of note, the patient was normotensive with a blood pressure of 120/81 mmHg. Best visual acuity sans correction was found to be 20/80 in the right eye and 20/40 in the left eye. Intraocular pressure and pupillary exam were both within normal limits. External examination revealed periorbital ecchymosis with trace edema, massive 360-degree hemorrhagic chemosis, and active bleeding from the subconjunctiva with overflow onto the patient's face (Fig. 1A, Fig. 1BA, B). Extraocular movements in the right eye were restricted 50% in all quadrants, while there were no restrictions in the left eye. Slit lamp and fundus examinations revealed no further abnormalities.Fig. 1A Right eye, upper lid manually retracted superiorly. Active extravasation and massive hemorrhagic chemosis can be seen, with blood overflowing the lower lid and draining down the patient's face.
Fig. 1A
Fig. 1B Extensive periorbital ecchymosis can be appreciated with inferior extension to the right jaw.
Fig. 1B
Laboratory workup was significant for an INR of 2.7 (normal range of 0.9–1.1, and 2.0–3.0 with therapeutic anticoagulation), a PT of 32.9 s (normal range of 12.1–15.1 s), and an initial hemoglobin of 14.3 g/dL which decreased to 13.6 g/dL 4 h later. Due to the active nature of the bleeding, a CT-Angiogram of the head with/without contrast was ordered, which revealed a small preseptal hematoma anterior to the right globe with a focus of active arterial extravasation of unclear source. No vascular malformations or large lacerations corresponding to the area of bleeding were noted. After discussion with the patient's internal medicine team, the decision was made to reverse the warfarin with 2.5 mg of Vitamin K and 1 unit of fresh frozen plasma. At this point, copious erythromycin ointment and pressure patches were applied to the right eye.
Several hours after admission the source of bleeding was identified as a small artery in the superficial inferonasal bulbar conjunctiva near the medial canthus and finally controlled with application of focal pressure patches for 25 and then 15 minutes. No additional management was necessary for several hours until the patient snorted and began actively bleeding again. Focal pressure patches were again applied to the source, twice for 30 minutes each, with subsequent hemostasis. Although surgical management and cautery were discussed with the patient, due to the recurrent severe bleeding, the patient was hesitant to pursue surgical measures and ultimately elected to continue patching upon further bleeding.
Regular ophthalmic examinations continued for two more days, with no further bleeding or ophthalmic complications, at which point the patient was cleared by Ophthalmology for discharge. The patient was medically managed for several more days due to episodes of atrial fibrillation and was discharged from the hospital five days after admission. At his final follow-up appointment, 3 months post-discharge, the patient had no recurrence of bleeding or other related complications, except for a mild contact dermatitis from the initial choice of antibiotic ointment. The patient's SCH and periorbital ecchymosis completely resolved over the course of follow-up and corrected vision in the right eye improved to baseline acuity of 20/40.
3 Discussion
This case demonstrates an atypically massive spontaneous SCH in a patient on therapeutic warfarin. With no reported trauma, previous occurrence of similar bleeds, or known lesions near the site of the bleed, this presentation is disproportionately severe and markedly inconsistent in magnitude compared to the expectedly small SCH in patients taking warfarin.4, 5, 6 While the exact cause of this patient's bleed may never be fully known, it is possible that the small bulbar vessel was initially damaged by a strong Valsalva maneuver since the patient denied any obvious trauma or eye rubbing. While the difference between therapeutic and supratherapeutic INR has not been shown to increase the risk of SCH in patients taking warfarin,1,5 the impressive amount of hemorrhage was certainly more suggestive of a further hypocoagulable state than the therapeutic INR found on laboratory examination. The only other documented case of warfarin cessation and reversal due solely to an SCH was in a patient with a supratherapeutic INR, further highlighting the distinctiveness of this presentation.8
Due to the lack of formal guidelines on managing an SCH of such atypical severity, clinical judgement was the sole determinant of management course. Discontinuation and reversal of warfarin was deemed necessary in this case due to the severity of the bleeding and mass effect on surrounding tissues. Had the bleeding not been so robust as to threaten the patient's vision, it may have been possible to manage the bleeding while maintaining anticoagulation. Once the bleeding vessel was identified, cautery versus surgical repair of the vessel was strongly considered due to the quantity of hemorrhage and fear of further recurrence leading to blood loss or visual impairment. However, due to the patient's choice for non-surgical management, conservative therapy with focal tamponade was further trialed with clear success as described. While the viability of anticoagulation reversal and conservative management of such a severe SCH is supported by this particular case report, it should be recognized as preliminary at this time. It may serve as an initial data point for future practitioners when faced with an SCH of this magnitude in an anticoagulated patient.
4 Conclusions
This case report highlights that, while extremely rare, spontaneous SCH in patients anticoagulated with warfarin may present with severity requiring focal tamponade, cessation and/or reversal of anticoagulation, or surgical management. To our knowledge, this is the first report to describe a warfarin-associated SCH of sufficient severity to require cessation and reversal of anticoagulation in a patient with a therapeutic INR. This report may also serve as a cautionary tale that even the most apparently benign condition, such as a SCH, can have atypical and severe presentations, and as such should not be dismissed without thorough examination or workup.
Patient consent
The patient provided both verbal and written consent for the use of his medical history and images to be written and submitted as a case report.
Funding
No funding or grant support.
Authorship
All authors attest that they meet the current ICMJE criteria.
Declaration of competing interest
None. | 2.5 MG DAILY WITH TWO DAYS OF 3.75 MG | DrugDosageText | CC BY-NC-ND | 33732947 | 19,061,275 | 2021-06 |
What was the outcome of reaction 'Conjunctival haemorrhage'? | Massive spontaneous subconjunctival hemorrhage in a patient on therapeutic warfarin: A case report.
To describe a case of massive spontaneous subconjunctival hemorrhage in a patient taking warfarin with a therapeutic international normalized ratio (INR).
Massive circumferential hemorrhagic chemosis, extensive periorbital and facial ecchymosis, and active arterial extravasation in the subconjunctiva which required cessation and reversal of anticoagulation. Findings gradually resolved over several months after discharge.
While subconjunctival hemorrhage, even in anticoagulated patients, is usually benign, rare examples of severe presentations exist. We present, to our knowledge, the first documented case of a subconjunctival hemorrhage necessitating cessation and reversal of anticoagulation in the setting of a therapeutic INR.
1 Introduction
Subconjunctival hemorrhage (SCH) is a typically benign process characterized by acute, painless bleeding into the subconjunctival space.1 It is a common ocular condition with risk factors that include hypertension, hyperlipidemia, diabetes mellitus, anticoagulation therapy, and increased age (particularly over 50-years old given the previously mentioned risk factors).2 While often spontaneous, SCH can be caused by Valsalva maneuvers, ocular and orbital trauma, and potentially serious systemic causes of coagulopathy.3 Warfarin, the most prescribed outpatient anticoagulant in North America, is a known cause of spontaneous SCH, with an incidence of 0.35–1.56%.4,5
While a supratherapeutic international normalized ratio (INR) has not been shown to increase the risk of SCH, patients on warfarin with SCH should have their INR and prothrombin time (PT) checked to evaluate systemic coagulation status.1,5 Warfarin-associated SCH usually resolves spontaneously after 5–10 days and rarely requires more than supportive care.5 Documented cases of severe warfarin-associated SCH requiring cessation of anticoagulation,6 cessation and surgical evacuation,7 or cessation and reversal of supratherapeutic anticoagulation are extremely rare in the literature.8 Usually, SCH are self-limiting, not overly severe, and do not require intervention. Therefore, formalized guidelines for proper anticoagulation management in warfarin-associated SCH do not exist and clinical judgement usually dictates treatment strategy.
Herein, we present a case that, to our knowledge, is the only reported occurrence of a warfarin-associated SCH in which the severity of presentation necessitated inpatient admission with cessation and reversal of anticoagulation in the setting of a therapeutic INR. This uniquely severe presentation of a condition universally regarded as benign provides the opportunity to examine the current literature regarding warfarin-associated SCH and offer insights to management strategies.
2 Case report
An 86-year-old Caucasian male presented to our institution's Emergency Department (ED) in May 2020 with progressive swelling and bleeding of his right eye with visual obstruction. His medical history was significant for hypertension, grade III chronic kidney disease, and atrial fibrillation. His ocular history was significant for bilateral cataract extractions with PCIOL implantation in 2013 and bilateral YAG laser capsulotomies in 2013. His medications were significant for Aspirin-CaCO3 81–300 mg daily, metoprolol ER 50 mg daily, and warfarin 2.5 mg daily with two days of 3.75 mg dosing. The rest of his history was non-contributory.
One week prior to presentation, the patient noticed an initially small, but slowly progressive, amount of blood overlying the sclera of his right eye. He eventually experienced slight obstruction of his vision from the blood as well as minor periorbital ecchymosis. Two days prior to presentation, the patient was diagnosed with a small SCH by an outside ophthalmologist and was instructed to discontinue his warfarin and was told to not worry about the bleeding. After two days of progressive bleeding, he presented to an outside hospital ED, where active subconjunctival bleeding and hemorrhagic chemosis were documented. Laboratory evaluation at that time showed an INR of 2.85 with a PT of 32.9. Due to this atypical presentation, the patient was referred to our institution for further management.
On presentation to our ED, the patient denied any pain, dizziness, blurry vision, or history of recent trauma to the eye or face. Of note, the patient was normotensive with a blood pressure of 120/81 mmHg. Best visual acuity sans correction was found to be 20/80 in the right eye and 20/40 in the left eye. Intraocular pressure and pupillary exam were both within normal limits. External examination revealed periorbital ecchymosis with trace edema, massive 360-degree hemorrhagic chemosis, and active bleeding from the subconjunctiva with overflow onto the patient's face (Fig. 1A, Fig. 1BA, B). Extraocular movements in the right eye were restricted 50% in all quadrants, while there were no restrictions in the left eye. Slit lamp and fundus examinations revealed no further abnormalities.Fig. 1A Right eye, upper lid manually retracted superiorly. Active extravasation and massive hemorrhagic chemosis can be seen, with blood overflowing the lower lid and draining down the patient's face.
Fig. 1A
Fig. 1B Extensive periorbital ecchymosis can be appreciated with inferior extension to the right jaw.
Fig. 1B
Laboratory workup was significant for an INR of 2.7 (normal range of 0.9–1.1, and 2.0–3.0 with therapeutic anticoagulation), a PT of 32.9 s (normal range of 12.1–15.1 s), and an initial hemoglobin of 14.3 g/dL which decreased to 13.6 g/dL 4 h later. Due to the active nature of the bleeding, a CT-Angiogram of the head with/without contrast was ordered, which revealed a small preseptal hematoma anterior to the right globe with a focus of active arterial extravasation of unclear source. No vascular malformations or large lacerations corresponding to the area of bleeding were noted. After discussion with the patient's internal medicine team, the decision was made to reverse the warfarin with 2.5 mg of Vitamin K and 1 unit of fresh frozen plasma. At this point, copious erythromycin ointment and pressure patches were applied to the right eye.
Several hours after admission the source of bleeding was identified as a small artery in the superficial inferonasal bulbar conjunctiva near the medial canthus and finally controlled with application of focal pressure patches for 25 and then 15 minutes. No additional management was necessary for several hours until the patient snorted and began actively bleeding again. Focal pressure patches were again applied to the source, twice for 30 minutes each, with subsequent hemostasis. Although surgical management and cautery were discussed with the patient, due to the recurrent severe bleeding, the patient was hesitant to pursue surgical measures and ultimately elected to continue patching upon further bleeding.
Regular ophthalmic examinations continued for two more days, with no further bleeding or ophthalmic complications, at which point the patient was cleared by Ophthalmology for discharge. The patient was medically managed for several more days due to episodes of atrial fibrillation and was discharged from the hospital five days after admission. At his final follow-up appointment, 3 months post-discharge, the patient had no recurrence of bleeding or other related complications, except for a mild contact dermatitis from the initial choice of antibiotic ointment. The patient's SCH and periorbital ecchymosis completely resolved over the course of follow-up and corrected vision in the right eye improved to baseline acuity of 20/40.
3 Discussion
This case demonstrates an atypically massive spontaneous SCH in a patient on therapeutic warfarin. With no reported trauma, previous occurrence of similar bleeds, or known lesions near the site of the bleed, this presentation is disproportionately severe and markedly inconsistent in magnitude compared to the expectedly small SCH in patients taking warfarin.4, 5, 6 While the exact cause of this patient's bleed may never be fully known, it is possible that the small bulbar vessel was initially damaged by a strong Valsalva maneuver since the patient denied any obvious trauma or eye rubbing. While the difference between therapeutic and supratherapeutic INR has not been shown to increase the risk of SCH in patients taking warfarin,1,5 the impressive amount of hemorrhage was certainly more suggestive of a further hypocoagulable state than the therapeutic INR found on laboratory examination. The only other documented case of warfarin cessation and reversal due solely to an SCH was in a patient with a supratherapeutic INR, further highlighting the distinctiveness of this presentation.8
Due to the lack of formal guidelines on managing an SCH of such atypical severity, clinical judgement was the sole determinant of management course. Discontinuation and reversal of warfarin was deemed necessary in this case due to the severity of the bleeding and mass effect on surrounding tissues. Had the bleeding not been so robust as to threaten the patient's vision, it may have been possible to manage the bleeding while maintaining anticoagulation. Once the bleeding vessel was identified, cautery versus surgical repair of the vessel was strongly considered due to the quantity of hemorrhage and fear of further recurrence leading to blood loss or visual impairment. However, due to the patient's choice for non-surgical management, conservative therapy with focal tamponade was further trialed with clear success as described. While the viability of anticoagulation reversal and conservative management of such a severe SCH is supported by this particular case report, it should be recognized as preliminary at this time. It may serve as an initial data point for future practitioners when faced with an SCH of this magnitude in an anticoagulated patient.
4 Conclusions
This case report highlights that, while extremely rare, spontaneous SCH in patients anticoagulated with warfarin may present with severity requiring focal tamponade, cessation and/or reversal of anticoagulation, or surgical management. To our knowledge, this is the first report to describe a warfarin-associated SCH of sufficient severity to require cessation and reversal of anticoagulation in a patient with a therapeutic INR. This report may also serve as a cautionary tale that even the most apparently benign condition, such as a SCH, can have atypical and severe presentations, and as such should not be dismissed without thorough examination or workup.
Patient consent
The patient provided both verbal and written consent for the use of his medical history and images to be written and submitted as a case report.
Funding
No funding or grant support.
Authorship
All authors attest that they meet the current ICMJE criteria.
Declaration of competing interest
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33732947 | 19,061,275 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus chorioretinitis'. | Cytomegalovirus retinitis following dexamethasone intravitreal implant.
To describe a case of Cytomegalovirus (CMV) Retinitis in an immunocompetent patient following Dexamethasone Intravitreal Implant (DII).
Retrospective chart review of a single patient. An 80-year-old immunocompetent male presented with floaters in his left eye 10 weeks after his DII. He was noted to have a visual acuity of 20/1200 in his left eye and a panuveitis with CMV retinitis. The patient underwent a vitreous biopsy and given immediate intravitreal foscarnet and an ongoing management regimen of oral valganciclovir for two months. His vision improved to 20/200 and his CMV retinitis resolved.
DII can trigger CMV retinitis in immunocompetent patients.
1 Introduction
We present a rare case of cytomegalovirus (CMV) retinitis in an immunocompetent patient following dexamethasone intravitreal implant (DII, Ozurdex®) injection.
2 Case report
An 80-year-old immunocompetent, non-diabetic male presented with a two-week history of left eye floaters and irritation 10 weeks following DII injection for neovascular age-related macular degeneration (AMD). The patient had previously been treated for 8 years with intravitreal anti-VEGF (ranibizumab and aflibercept) and photodynamic therapy however the choroidal neovascularisation (CNV) had become refractory to these therapies with persistent exudation. The eye had previously been vitrectomised for a retinal detachment, resulting in a reduced half-life of intravitreal anti-VEGF. Although unconventional, DII had resulted in improvement in exudation, and 6 injections had been administered over the preceding 2 years. His past medical history included asthma, prior curative radiotherapy for prostate cancer with some residual mild renal impairment.
On examination his best corrected visual acuity had dropped to 20/1200 in his left eye (OS) from 20/160 on the previous review. The intraocular pressure was 13 mmHg OS. The left eye revealed a mild ciliary flush, fine keratic precipitates, 3+ cells in the anterior chamber, a well-positioned posterior chamber intraocular lens, moderate vitritis and white retinitis associated with peripheral scattered retinal haemorrhages in the nasal and superior quadrants, posterior pole and inferior to the inferior retinal vascular arcade (Fig. 1A). Examination of the right eye was unremarkable.Fig. 1 A) Colour fundus photograph of the left eye on presentation demonstrating active CMV retinitis in the superior and nasal quadrants, posterior pole and inferior to the inferior retinal vascular arcade. The supero-temporal quadrant has a white scar from previous cryotherapy and laser applied during vitrectomy surgery for a retinal detachment 20 years prior. B) Following two months of intravitreal foscarnet and oral valganciclovir, there has been resolution of the CMV retinitis with mild residual pigmentary changes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
A provisional diagnosis of viral retinitis was made and the patient underwent an urgent vitreous cavity pars plana biopsy with a 25-gauge needle which was positive for CMV on polymerase chain reaction (PCR). The specimen was negative for Herpes simplex virus, Varicella zoster virus, toxoplasmosis PCR and microbiological cultures. CMV serology revealed a positive IgG result and a negative IgM result for CMV. CMV DNA PCR on serum is not available at our centre. Syphilis and HIV serology were negative. No Systemic signs of CMV infection were found. Immediate medical treatment included intravitreal foscarnet 2.4mg in 0.1ml as well as oral valganciclovir at a reduced induction dosage of 450mg twice daily due to a prior history of renal impairment (serum creatinine of 122 μmol/L at baseline).
Following a two-month course of oral valganciclovir his vision improved back to 20/200 with resolution of the CMV retinitis (Fig. 1B). He did not require any further intravitreal foscarnet after the initial dose. He was referred to an immunologist, who performed a thorough systemic screen including exclusion of infectious causes, urine analysis, autoimmune serology including IgG subclasses and haematological screens. None of these screens revealed any abnormalities that could have predisposed this patient to any cellular or antibody immunodeficiency.
3 Discussion
CMV retinitis is one of the most common opportunistic ocular infections, usually seen in immunocompromised patients.1, 2, 3 Rarely, CMV retinitis can occur in immunocompetent patients.4, 5, 6 Presentation of disease in immunocompetent patients with CMV retinitis more frequently presents with a marked inflammatory response including vitritis, a finding also noted in this case.4,7 Recently, the use of localised intravitreal or periocular steroids agents, such as triamcinolone acetonide, has been suggested to be an additional risk factor in developing CMV retinitis in both immunosuppressed and immunocompetent patients.2,8 The advent of the DII (Ozurdex®) has helped treat macular oedema due to diabetes, posterior non-infectious uveitis, retinal vein occlusions and choroidal neovascularisation secondary to age-related macular degeneration.9,10 Steroids are known immunosuppressive agents that work through sequestering CD4 T cells alongside inhibiting the transcription of cytokines.11 It is possible that the DII caused enough local immunosuppression to trigger retinal CMV infection.
A thorough MEDLINE and PubMed search revealed four cases in English print journals of patients that underwent DII and subsequently developed CMV retinitis.5,12, 13, 14 Two of these cases were patients who were systemically immunosuppressed due to underlying conditions such as a renal transplant and retinal vasculitis.13,14 A third case was described as being in an immunocompetent patient but they had a 25-year history of type 2 diabetes.12 In the fourth case, the medical history of the patient was not clearly described, such that it is impossible to verify if the patient was definitely immunocompetent.5 In our case, systemic immunosuppression was definitively excluded by an immunologist. The patient's past medical history was not thought to be contributory.
One factor that may have contributed to the development of CMV retinitis is the patient's elderly age. Immunosenescence refers to the impaired ability of the body's immune system to respond to various triggers with increasing age.15,16 CD4 helper T cell proliferation reduces with age17 and there is an age associated increase in the prevalence CMV infections.18 Regardless, spontaneous CMV retinitis in immunocompetent patients is rare, and the DII is likely to be major contributing factor.
4 Conclusion
DII is a useful treatment for many forms of macular oedema, but CMV retinitis should be added to the potential side effects, even in the immunocompetent patient.
Patient consent
The patient has provided written consent for publication of their case in AJO.
Funding
No funding or grant support.
Intellectual property
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
Research ethics
Written consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).
Authorship
All listed authors meet the ICMJE criteria.
We attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.
Declaration of competing interest
No conflict of interest exists.
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements
Nil. | DEXAMETHASONE | DrugsGivenReaction | CC BY-NC-ND | 33732951 | 19,069,371 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Cytomegalovirus retinitis following dexamethasone intravitreal implant.
To describe a case of Cytomegalovirus (CMV) Retinitis in an immunocompetent patient following Dexamethasone Intravitreal Implant (DII).
Retrospective chart review of a single patient. An 80-year-old immunocompetent male presented with floaters in his left eye 10 weeks after his DII. He was noted to have a visual acuity of 20/1200 in his left eye and a panuveitis with CMV retinitis. The patient underwent a vitreous biopsy and given immediate intravitreal foscarnet and an ongoing management regimen of oral valganciclovir for two months. His vision improved to 20/200 and his CMV retinitis resolved.
DII can trigger CMV retinitis in immunocompetent patients.
1 Introduction
We present a rare case of cytomegalovirus (CMV) retinitis in an immunocompetent patient following dexamethasone intravitreal implant (DII, Ozurdex®) injection.
2 Case report
An 80-year-old immunocompetent, non-diabetic male presented with a two-week history of left eye floaters and irritation 10 weeks following DII injection for neovascular age-related macular degeneration (AMD). The patient had previously been treated for 8 years with intravitreal anti-VEGF (ranibizumab and aflibercept) and photodynamic therapy however the choroidal neovascularisation (CNV) had become refractory to these therapies with persistent exudation. The eye had previously been vitrectomised for a retinal detachment, resulting in a reduced half-life of intravitreal anti-VEGF. Although unconventional, DII had resulted in improvement in exudation, and 6 injections had been administered over the preceding 2 years. His past medical history included asthma, prior curative radiotherapy for prostate cancer with some residual mild renal impairment.
On examination his best corrected visual acuity had dropped to 20/1200 in his left eye (OS) from 20/160 on the previous review. The intraocular pressure was 13 mmHg OS. The left eye revealed a mild ciliary flush, fine keratic precipitates, 3+ cells in the anterior chamber, a well-positioned posterior chamber intraocular lens, moderate vitritis and white retinitis associated with peripheral scattered retinal haemorrhages in the nasal and superior quadrants, posterior pole and inferior to the inferior retinal vascular arcade (Fig. 1A). Examination of the right eye was unremarkable.Fig. 1 A) Colour fundus photograph of the left eye on presentation demonstrating active CMV retinitis in the superior and nasal quadrants, posterior pole and inferior to the inferior retinal vascular arcade. The supero-temporal quadrant has a white scar from previous cryotherapy and laser applied during vitrectomy surgery for a retinal detachment 20 years prior. B) Following two months of intravitreal foscarnet and oral valganciclovir, there has been resolution of the CMV retinitis with mild residual pigmentary changes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
A provisional diagnosis of viral retinitis was made and the patient underwent an urgent vitreous cavity pars plana biopsy with a 25-gauge needle which was positive for CMV on polymerase chain reaction (PCR). The specimen was negative for Herpes simplex virus, Varicella zoster virus, toxoplasmosis PCR and microbiological cultures. CMV serology revealed a positive IgG result and a negative IgM result for CMV. CMV DNA PCR on serum is not available at our centre. Syphilis and HIV serology were negative. No Systemic signs of CMV infection were found. Immediate medical treatment included intravitreal foscarnet 2.4mg in 0.1ml as well as oral valganciclovir at a reduced induction dosage of 450mg twice daily due to a prior history of renal impairment (serum creatinine of 122 μmol/L at baseline).
Following a two-month course of oral valganciclovir his vision improved back to 20/200 with resolution of the CMV retinitis (Fig. 1B). He did not require any further intravitreal foscarnet after the initial dose. He was referred to an immunologist, who performed a thorough systemic screen including exclusion of infectious causes, urine analysis, autoimmune serology including IgG subclasses and haematological screens. None of these screens revealed any abnormalities that could have predisposed this patient to any cellular or antibody immunodeficiency.
3 Discussion
CMV retinitis is one of the most common opportunistic ocular infections, usually seen in immunocompromised patients.1, 2, 3 Rarely, CMV retinitis can occur in immunocompetent patients.4, 5, 6 Presentation of disease in immunocompetent patients with CMV retinitis more frequently presents with a marked inflammatory response including vitritis, a finding also noted in this case.4,7 Recently, the use of localised intravitreal or periocular steroids agents, such as triamcinolone acetonide, has been suggested to be an additional risk factor in developing CMV retinitis in both immunosuppressed and immunocompetent patients.2,8 The advent of the DII (Ozurdex®) has helped treat macular oedema due to diabetes, posterior non-infectious uveitis, retinal vein occlusions and choroidal neovascularisation secondary to age-related macular degeneration.9,10 Steroids are known immunosuppressive agents that work through sequestering CD4 T cells alongside inhibiting the transcription of cytokines.11 It is possible that the DII caused enough local immunosuppression to trigger retinal CMV infection.
A thorough MEDLINE and PubMed search revealed four cases in English print journals of patients that underwent DII and subsequently developed CMV retinitis.5,12, 13, 14 Two of these cases were patients who were systemically immunosuppressed due to underlying conditions such as a renal transplant and retinal vasculitis.13,14 A third case was described as being in an immunocompetent patient but they had a 25-year history of type 2 diabetes.12 In the fourth case, the medical history of the patient was not clearly described, such that it is impossible to verify if the patient was definitely immunocompetent.5 In our case, systemic immunosuppression was definitively excluded by an immunologist. The patient's past medical history was not thought to be contributory.
One factor that may have contributed to the development of CMV retinitis is the patient's elderly age. Immunosenescence refers to the impaired ability of the body's immune system to respond to various triggers with increasing age.15,16 CD4 helper T cell proliferation reduces with age17 and there is an age associated increase in the prevalence CMV infections.18 Regardless, spontaneous CMV retinitis in immunocompetent patients is rare, and the DII is likely to be major contributing factor.
4 Conclusion
DII is a useful treatment for many forms of macular oedema, but CMV retinitis should be added to the potential side effects, even in the immunocompetent patient.
Patient consent
The patient has provided written consent for publication of their case in AJO.
Funding
No funding or grant support.
Intellectual property
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
Research ethics
Written consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).
Authorship
All listed authors meet the ICMJE criteria.
We attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.
Declaration of competing interest
No conflict of interest exists.
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements
Nil. | DEXAMETHASONE | DrugsGivenReaction | CC BY-NC-ND | 33732951 | 19,069,371 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Uveitis'. | Cytomegalovirus retinitis following dexamethasone intravitreal implant.
To describe a case of Cytomegalovirus (CMV) Retinitis in an immunocompetent patient following Dexamethasone Intravitreal Implant (DII).
Retrospective chart review of a single patient. An 80-year-old immunocompetent male presented with floaters in his left eye 10 weeks after his DII. He was noted to have a visual acuity of 20/1200 in his left eye and a panuveitis with CMV retinitis. The patient underwent a vitreous biopsy and given immediate intravitreal foscarnet and an ongoing management regimen of oral valganciclovir for two months. His vision improved to 20/200 and his CMV retinitis resolved.
DII can trigger CMV retinitis in immunocompetent patients.
1 Introduction
We present a rare case of cytomegalovirus (CMV) retinitis in an immunocompetent patient following dexamethasone intravitreal implant (DII, Ozurdex®) injection.
2 Case report
An 80-year-old immunocompetent, non-diabetic male presented with a two-week history of left eye floaters and irritation 10 weeks following DII injection for neovascular age-related macular degeneration (AMD). The patient had previously been treated for 8 years with intravitreal anti-VEGF (ranibizumab and aflibercept) and photodynamic therapy however the choroidal neovascularisation (CNV) had become refractory to these therapies with persistent exudation. The eye had previously been vitrectomised for a retinal detachment, resulting in a reduced half-life of intravitreal anti-VEGF. Although unconventional, DII had resulted in improvement in exudation, and 6 injections had been administered over the preceding 2 years. His past medical history included asthma, prior curative radiotherapy for prostate cancer with some residual mild renal impairment.
On examination his best corrected visual acuity had dropped to 20/1200 in his left eye (OS) from 20/160 on the previous review. The intraocular pressure was 13 mmHg OS. The left eye revealed a mild ciliary flush, fine keratic precipitates, 3+ cells in the anterior chamber, a well-positioned posterior chamber intraocular lens, moderate vitritis and white retinitis associated with peripheral scattered retinal haemorrhages in the nasal and superior quadrants, posterior pole and inferior to the inferior retinal vascular arcade (Fig. 1A). Examination of the right eye was unremarkable.Fig. 1 A) Colour fundus photograph of the left eye on presentation demonstrating active CMV retinitis in the superior and nasal quadrants, posterior pole and inferior to the inferior retinal vascular arcade. The supero-temporal quadrant has a white scar from previous cryotherapy and laser applied during vitrectomy surgery for a retinal detachment 20 years prior. B) Following two months of intravitreal foscarnet and oral valganciclovir, there has been resolution of the CMV retinitis with mild residual pigmentary changes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
A provisional diagnosis of viral retinitis was made and the patient underwent an urgent vitreous cavity pars plana biopsy with a 25-gauge needle which was positive for CMV on polymerase chain reaction (PCR). The specimen was negative for Herpes simplex virus, Varicella zoster virus, toxoplasmosis PCR and microbiological cultures. CMV serology revealed a positive IgG result and a negative IgM result for CMV. CMV DNA PCR on serum is not available at our centre. Syphilis and HIV serology were negative. No Systemic signs of CMV infection were found. Immediate medical treatment included intravitreal foscarnet 2.4mg in 0.1ml as well as oral valganciclovir at a reduced induction dosage of 450mg twice daily due to a prior history of renal impairment (serum creatinine of 122 μmol/L at baseline).
Following a two-month course of oral valganciclovir his vision improved back to 20/200 with resolution of the CMV retinitis (Fig. 1B). He did not require any further intravitreal foscarnet after the initial dose. He was referred to an immunologist, who performed a thorough systemic screen including exclusion of infectious causes, urine analysis, autoimmune serology including IgG subclasses and haematological screens. None of these screens revealed any abnormalities that could have predisposed this patient to any cellular or antibody immunodeficiency.
3 Discussion
CMV retinitis is one of the most common opportunistic ocular infections, usually seen in immunocompromised patients.1, 2, 3 Rarely, CMV retinitis can occur in immunocompetent patients.4, 5, 6 Presentation of disease in immunocompetent patients with CMV retinitis more frequently presents with a marked inflammatory response including vitritis, a finding also noted in this case.4,7 Recently, the use of localised intravitreal or periocular steroids agents, such as triamcinolone acetonide, has been suggested to be an additional risk factor in developing CMV retinitis in both immunosuppressed and immunocompetent patients.2,8 The advent of the DII (Ozurdex®) has helped treat macular oedema due to diabetes, posterior non-infectious uveitis, retinal vein occlusions and choroidal neovascularisation secondary to age-related macular degeneration.9,10 Steroids are known immunosuppressive agents that work through sequestering CD4 T cells alongside inhibiting the transcription of cytokines.11 It is possible that the DII caused enough local immunosuppression to trigger retinal CMV infection.
A thorough MEDLINE and PubMed search revealed four cases in English print journals of patients that underwent DII and subsequently developed CMV retinitis.5,12, 13, 14 Two of these cases were patients who were systemically immunosuppressed due to underlying conditions such as a renal transplant and retinal vasculitis.13,14 A third case was described as being in an immunocompetent patient but they had a 25-year history of type 2 diabetes.12 In the fourth case, the medical history of the patient was not clearly described, such that it is impossible to verify if the patient was definitely immunocompetent.5 In our case, systemic immunosuppression was definitively excluded by an immunologist. The patient's past medical history was not thought to be contributory.
One factor that may have contributed to the development of CMV retinitis is the patient's elderly age. Immunosenescence refers to the impaired ability of the body's immune system to respond to various triggers with increasing age.15,16 CD4 helper T cell proliferation reduces with age17 and there is an age associated increase in the prevalence CMV infections.18 Regardless, spontaneous CMV retinitis in immunocompetent patients is rare, and the DII is likely to be major contributing factor.
4 Conclusion
DII is a useful treatment for many forms of macular oedema, but CMV retinitis should be added to the potential side effects, even in the immunocompetent patient.
Patient consent
The patient has provided written consent for publication of their case in AJO.
Funding
No funding or grant support.
Intellectual property
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
Research ethics
Written consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).
Authorship
All listed authors meet the ICMJE criteria.
We attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.
Declaration of competing interest
No conflict of interest exists.
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements
Nil. | DEXAMETHASONE | DrugsGivenReaction | CC BY-NC-ND | 33732951 | 19,069,371 | 2021-06 |
What was the administration route of drug 'DEXAMETHASONE'? | Cytomegalovirus retinitis following dexamethasone intravitreal implant.
To describe a case of Cytomegalovirus (CMV) Retinitis in an immunocompetent patient following Dexamethasone Intravitreal Implant (DII).
Retrospective chart review of a single patient. An 80-year-old immunocompetent male presented with floaters in his left eye 10 weeks after his DII. He was noted to have a visual acuity of 20/1200 in his left eye and a panuveitis with CMV retinitis. The patient underwent a vitreous biopsy and given immediate intravitreal foscarnet and an ongoing management regimen of oral valganciclovir for two months. His vision improved to 20/200 and his CMV retinitis resolved.
DII can trigger CMV retinitis in immunocompetent patients.
1 Introduction
We present a rare case of cytomegalovirus (CMV) retinitis in an immunocompetent patient following dexamethasone intravitreal implant (DII, Ozurdex®) injection.
2 Case report
An 80-year-old immunocompetent, non-diabetic male presented with a two-week history of left eye floaters and irritation 10 weeks following DII injection for neovascular age-related macular degeneration (AMD). The patient had previously been treated for 8 years with intravitreal anti-VEGF (ranibizumab and aflibercept) and photodynamic therapy however the choroidal neovascularisation (CNV) had become refractory to these therapies with persistent exudation. The eye had previously been vitrectomised for a retinal detachment, resulting in a reduced half-life of intravitreal anti-VEGF. Although unconventional, DII had resulted in improvement in exudation, and 6 injections had been administered over the preceding 2 years. His past medical history included asthma, prior curative radiotherapy for prostate cancer with some residual mild renal impairment.
On examination his best corrected visual acuity had dropped to 20/1200 in his left eye (OS) from 20/160 on the previous review. The intraocular pressure was 13 mmHg OS. The left eye revealed a mild ciliary flush, fine keratic precipitates, 3+ cells in the anterior chamber, a well-positioned posterior chamber intraocular lens, moderate vitritis and white retinitis associated with peripheral scattered retinal haemorrhages in the nasal and superior quadrants, posterior pole and inferior to the inferior retinal vascular arcade (Fig. 1A). Examination of the right eye was unremarkable.Fig. 1 A) Colour fundus photograph of the left eye on presentation demonstrating active CMV retinitis in the superior and nasal quadrants, posterior pole and inferior to the inferior retinal vascular arcade. The supero-temporal quadrant has a white scar from previous cryotherapy and laser applied during vitrectomy surgery for a retinal detachment 20 years prior. B) Following two months of intravitreal foscarnet and oral valganciclovir, there has been resolution of the CMV retinitis with mild residual pigmentary changes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
A provisional diagnosis of viral retinitis was made and the patient underwent an urgent vitreous cavity pars plana biopsy with a 25-gauge needle which was positive for CMV on polymerase chain reaction (PCR). The specimen was negative for Herpes simplex virus, Varicella zoster virus, toxoplasmosis PCR and microbiological cultures. CMV serology revealed a positive IgG result and a negative IgM result for CMV. CMV DNA PCR on serum is not available at our centre. Syphilis and HIV serology were negative. No Systemic signs of CMV infection were found. Immediate medical treatment included intravitreal foscarnet 2.4mg in 0.1ml as well as oral valganciclovir at a reduced induction dosage of 450mg twice daily due to a prior history of renal impairment (serum creatinine of 122 μmol/L at baseline).
Following a two-month course of oral valganciclovir his vision improved back to 20/200 with resolution of the CMV retinitis (Fig. 1B). He did not require any further intravitreal foscarnet after the initial dose. He was referred to an immunologist, who performed a thorough systemic screen including exclusion of infectious causes, urine analysis, autoimmune serology including IgG subclasses and haematological screens. None of these screens revealed any abnormalities that could have predisposed this patient to any cellular or antibody immunodeficiency.
3 Discussion
CMV retinitis is one of the most common opportunistic ocular infections, usually seen in immunocompromised patients.1, 2, 3 Rarely, CMV retinitis can occur in immunocompetent patients.4, 5, 6 Presentation of disease in immunocompetent patients with CMV retinitis more frequently presents with a marked inflammatory response including vitritis, a finding also noted in this case.4,7 Recently, the use of localised intravitreal or periocular steroids agents, such as triamcinolone acetonide, has been suggested to be an additional risk factor in developing CMV retinitis in both immunosuppressed and immunocompetent patients.2,8 The advent of the DII (Ozurdex®) has helped treat macular oedema due to diabetes, posterior non-infectious uveitis, retinal vein occlusions and choroidal neovascularisation secondary to age-related macular degeneration.9,10 Steroids are known immunosuppressive agents that work through sequestering CD4 T cells alongside inhibiting the transcription of cytokines.11 It is possible that the DII caused enough local immunosuppression to trigger retinal CMV infection.
A thorough MEDLINE and PubMed search revealed four cases in English print journals of patients that underwent DII and subsequently developed CMV retinitis.5,12, 13, 14 Two of these cases were patients who were systemically immunosuppressed due to underlying conditions such as a renal transplant and retinal vasculitis.13,14 A third case was described as being in an immunocompetent patient but they had a 25-year history of type 2 diabetes.12 In the fourth case, the medical history of the patient was not clearly described, such that it is impossible to verify if the patient was definitely immunocompetent.5 In our case, systemic immunosuppression was definitively excluded by an immunologist. The patient's past medical history was not thought to be contributory.
One factor that may have contributed to the development of CMV retinitis is the patient's elderly age. Immunosenescence refers to the impaired ability of the body's immune system to respond to various triggers with increasing age.15,16 CD4 helper T cell proliferation reduces with age17 and there is an age associated increase in the prevalence CMV infections.18 Regardless, spontaneous CMV retinitis in immunocompetent patients is rare, and the DII is likely to be major contributing factor.
4 Conclusion
DII is a useful treatment for many forms of macular oedema, but CMV retinitis should be added to the potential side effects, even in the immunocompetent patient.
Patient consent
The patient has provided written consent for publication of their case in AJO.
Funding
No funding or grant support.
Intellectual property
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
Research ethics
Written consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).
Authorship
All listed authors meet the ICMJE criteria.
We attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.
Declaration of competing interest
No conflict of interest exists.
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements
Nil. | Intraocular | DrugAdministrationRoute | CC BY-NC-ND | 33732951 | 19,069,371 | 2021-06 |
What was the outcome of reaction 'Cytomegalovirus chorioretinitis'? | Cytomegalovirus retinitis following dexamethasone intravitreal implant.
To describe a case of Cytomegalovirus (CMV) Retinitis in an immunocompetent patient following Dexamethasone Intravitreal Implant (DII).
Retrospective chart review of a single patient. An 80-year-old immunocompetent male presented with floaters in his left eye 10 weeks after his DII. He was noted to have a visual acuity of 20/1200 in his left eye and a panuveitis with CMV retinitis. The patient underwent a vitreous biopsy and given immediate intravitreal foscarnet and an ongoing management regimen of oral valganciclovir for two months. His vision improved to 20/200 and his CMV retinitis resolved.
DII can trigger CMV retinitis in immunocompetent patients.
1 Introduction
We present a rare case of cytomegalovirus (CMV) retinitis in an immunocompetent patient following dexamethasone intravitreal implant (DII, Ozurdex®) injection.
2 Case report
An 80-year-old immunocompetent, non-diabetic male presented with a two-week history of left eye floaters and irritation 10 weeks following DII injection for neovascular age-related macular degeneration (AMD). The patient had previously been treated for 8 years with intravitreal anti-VEGF (ranibizumab and aflibercept) and photodynamic therapy however the choroidal neovascularisation (CNV) had become refractory to these therapies with persistent exudation. The eye had previously been vitrectomised for a retinal detachment, resulting in a reduced half-life of intravitreal anti-VEGF. Although unconventional, DII had resulted in improvement in exudation, and 6 injections had been administered over the preceding 2 years. His past medical history included asthma, prior curative radiotherapy for prostate cancer with some residual mild renal impairment.
On examination his best corrected visual acuity had dropped to 20/1200 in his left eye (OS) from 20/160 on the previous review. The intraocular pressure was 13 mmHg OS. The left eye revealed a mild ciliary flush, fine keratic precipitates, 3+ cells in the anterior chamber, a well-positioned posterior chamber intraocular lens, moderate vitritis and white retinitis associated with peripheral scattered retinal haemorrhages in the nasal and superior quadrants, posterior pole and inferior to the inferior retinal vascular arcade (Fig. 1A). Examination of the right eye was unremarkable.Fig. 1 A) Colour fundus photograph of the left eye on presentation demonstrating active CMV retinitis in the superior and nasal quadrants, posterior pole and inferior to the inferior retinal vascular arcade. The supero-temporal quadrant has a white scar from previous cryotherapy and laser applied during vitrectomy surgery for a retinal detachment 20 years prior. B) Following two months of intravitreal foscarnet and oral valganciclovir, there has been resolution of the CMV retinitis with mild residual pigmentary changes. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 1
A provisional diagnosis of viral retinitis was made and the patient underwent an urgent vitreous cavity pars plana biopsy with a 25-gauge needle which was positive for CMV on polymerase chain reaction (PCR). The specimen was negative for Herpes simplex virus, Varicella zoster virus, toxoplasmosis PCR and microbiological cultures. CMV serology revealed a positive IgG result and a negative IgM result for CMV. CMV DNA PCR on serum is not available at our centre. Syphilis and HIV serology were negative. No Systemic signs of CMV infection were found. Immediate medical treatment included intravitreal foscarnet 2.4mg in 0.1ml as well as oral valganciclovir at a reduced induction dosage of 450mg twice daily due to a prior history of renal impairment (serum creatinine of 122 μmol/L at baseline).
Following a two-month course of oral valganciclovir his vision improved back to 20/200 with resolution of the CMV retinitis (Fig. 1B). He did not require any further intravitreal foscarnet after the initial dose. He was referred to an immunologist, who performed a thorough systemic screen including exclusion of infectious causes, urine analysis, autoimmune serology including IgG subclasses and haematological screens. None of these screens revealed any abnormalities that could have predisposed this patient to any cellular or antibody immunodeficiency.
3 Discussion
CMV retinitis is one of the most common opportunistic ocular infections, usually seen in immunocompromised patients.1, 2, 3 Rarely, CMV retinitis can occur in immunocompetent patients.4, 5, 6 Presentation of disease in immunocompetent patients with CMV retinitis more frequently presents with a marked inflammatory response including vitritis, a finding also noted in this case.4,7 Recently, the use of localised intravitreal or periocular steroids agents, such as triamcinolone acetonide, has been suggested to be an additional risk factor in developing CMV retinitis in both immunosuppressed and immunocompetent patients.2,8 The advent of the DII (Ozurdex®) has helped treat macular oedema due to diabetes, posterior non-infectious uveitis, retinal vein occlusions and choroidal neovascularisation secondary to age-related macular degeneration.9,10 Steroids are known immunosuppressive agents that work through sequestering CD4 T cells alongside inhibiting the transcription of cytokines.11 It is possible that the DII caused enough local immunosuppression to trigger retinal CMV infection.
A thorough MEDLINE and PubMed search revealed four cases in English print journals of patients that underwent DII and subsequently developed CMV retinitis.5,12, 13, 14 Two of these cases were patients who were systemically immunosuppressed due to underlying conditions such as a renal transplant and retinal vasculitis.13,14 A third case was described as being in an immunocompetent patient but they had a 25-year history of type 2 diabetes.12 In the fourth case, the medical history of the patient was not clearly described, such that it is impossible to verify if the patient was definitely immunocompetent.5 In our case, systemic immunosuppression was definitively excluded by an immunologist. The patient's past medical history was not thought to be contributory.
One factor that may have contributed to the development of CMV retinitis is the patient's elderly age. Immunosenescence refers to the impaired ability of the body's immune system to respond to various triggers with increasing age.15,16 CD4 helper T cell proliferation reduces with age17 and there is an age associated increase in the prevalence CMV infections.18 Regardless, spontaneous CMV retinitis in immunocompetent patients is rare, and the DII is likely to be major contributing factor.
4 Conclusion
DII is a useful treatment for many forms of macular oedema, but CMV retinitis should be added to the potential side effects, even in the immunocompetent patient.
Patient consent
The patient has provided written consent for publication of their case in AJO.
Funding
No funding or grant support.
Intellectual property
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
Research ethics
Written consent to publish potentially identifying information, such as details or the case and photographs, was obtained from the patient(s) or their legal guardian(s).
Authorship
All listed authors meet the ICMJE criteria.
We attest that all authors contributed significantly to the creation of this manuscript, each having fulfilled criteria as established by the ICMJE.
Declaration of competing interest
No conflict of interest exists.
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgements
Nil. | Recovered | ReactionOutcome | CC BY-NC-ND | 33732951 | 19,069,371 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Chronic endophthalmitis from Aquamicrobium lusatiense.
To report a case of chronic endophthalmitis caused by Aquamicrobium lusatiense following phacoemulsification surgery.
A 71 year-old woman was referred for chronic ocular inflammation after cataract surgery. Serologic testing was negative for common infectious etiologies. Her condition deteriorated on immune-modulating therapy prompting vitreous biopsy, which confirmed infection with A. lusatiense. She was managed successfully with intravitreal antibiotic pharmacotherapy and intraocular lens explantation.
This is the first reported case of A. lusatiense causing endophthalmitis, or disease in a human, in the literature.
1 Introduction
Chronic postoperative endophthalmitis is a vision-threatening complication of ophthalmic surgery that can be caused by a range of organisms, from Propionibacterium acnes, to Staphylococcus epidermidis, to other atypical bacteria and select fungal species.1,2 These cases often pose a diagnostic challenge, typically presenting with smoldering inflammation, which can respond initially to corticosteroid therapy. Herein we describe the first case of Aquamicrobium lusatiense causing endophthalmitis, or indeed, disease in a human, in the English language literature.
2 Case report
A 71 year-old immunocompetent Caucasian woman underwent uncomplicated phacoemulsification surgery with an outside provider. Immediately following surgery, Snellen visual acuity was measured at 20/20. At the one-month post-operative visit, anterior chamber cell was noted, and she was treated with topical 0.1% preservative-free dexamethasone due to a self-reported allergy to 1% prednisolone acetate. After completing a taper, she presented with rebound inflammation and was treated with twice daily 0.05% difluprednate for three days before transitioning back to 0.1% dexamethasone, remaining on twice daily dosing for maintenance. At her six-month follow-up visit she underwent yttrium-aluminum-garnet (YAG) laser posterior capsulotomy without complication. Sixteen months after cataract surgery, she transferred care to a new provider who tapered her off dexamethasone drops. She returned one month later with acute-onset unilateral hypopyon uveitis with a visual acuity of 20/400 and was initiated on topical 0.05% difluprednate every 2 hours and referred for evaluation to the retina service at Vanderbilt Eye Institute.
Initial examination showed mild corneal edema with diffuse, pigmented keratic precipitates and 3+ anterior chamber cell in the right eye. The vitreous was clear and there was no macular edema on optical coherence tomography (OCT). Serologic testing for treponemal IgG, herpes simplex virus (HSV) type 1 and 2 IgM, quantiferon gold, and Lyme ELISA were negative. Chest radiography was normal. Due to the corneal edema and pigmented keratic precipitates, herpetic etiology remained high on the differential. Therefore, empiric oral valacyclovir was started and difluprednate slowly tapered. One month later she returned with 20/60 visual acuity. The anterior chamber was quiet, and she transitioned to 0.1% fluorometholone taper. She returned two months later with stable exam findings but reported that she had flared twice and resumed difluprednate after consultation with an outside provider. Oral prednisone and 15 mg weekly methotrexate were started. Her disease quieted and vision improved to 20/50, but two months after initiation of methotrexate visual acuity deteriorated to 20/150, and examination showed 1+ anterior chamber cell and 2+ vitreous cell. Methotrexate was increased to 25 mg weekly. One month later, her vision improved to 20/70, but she remained active, with 2+ anterior chamber and vitreous cell, and was started on adalimumab 40mg every other week.
Following initiation of adalimumab, her visual acuity deteriorated to count fingers. Slit lamp examination showed increase in keratic precipitates (Fig. 1A) with a hazy view of the anterior and posterior chambers. B-scan ultrasonography demonstrated hyperechoic vitreous opacities concerning for vitritis (Fig. 1B). Her inflammation continued to worsen despite immunosuppression, and a diagnostic vitrectomy was performed.Fig. 1 (A) Slit-lamp photograph of the right eye during demonstrating diffuse pigmented keratic precipitates and hazy anterior chamber. (B) B-scan ultrasonography, transverse scan at 3 o'clock demonstrating posterior vitreous detachment with hyperechoic vitreous opacities.
Fig. 1
Intraoperatively, polymerase chain reaction (PCR) testing of aqueous for HSV 1 and 2, varicella zoster virus, and cytomegalovirus was negative. Vitreous biopsy and biopsy of the posterior capsule were sent for microbiology and the patient was treated with 1mg intravitreal vancomycin due to suspicion for P. acnes endophthalmitis. Cultures from vitreous and posterior capsule demonstrated light growth of a Gram-negative rod that was sent to the Tennessee state laboratory for identification. The state laboratory identified the organism as A. lusatiense.
Immune modulating therapy was discontinued, and the patient underwent repeat vitrectomy with explantation of the intraocular lens as well as intravitreal injections of 2mg ceftazidine and 160μg moxifloxacin to cover the Gram negative organism. Additionally, she was treated with six months of oral ciprofloxacin 500mg daily. She continued to improve; two months after completion of her course of ciprofloxacin, the eye remained quiet and a scleral fixated intraocular lens was placed. One year after diagnostic vitrectomy at her most recent follow-up, the keratic precipitates, anterior chamber cell, and vitreous cell had resolved (Fig. 2), and best-corrected Snellen visual acuity was measured at 20/30–2.Fig. 2 Slit lamp photograph of the right eye after intraocular lens explantation and one month of oral ciprofloxacin showing complete resolution of pigmented keratic precipitates in a quiet eye.
Fig. 2
3 Discussion
A. lusatiense is an aerobic Gram-negative, catalase- and oxidase-positive rod. Formerly Defluvibacter lusatiensis, the species was first described in 1999 after isolation from waste water.3 The organism was transferred to the Aquamicrobium genus in 2009 due to genetic similarity to A. defluvii.4 While Aquamicrobium spp. are most commonly isolated from waste water, they have also been identified in contaminated soil and in tidal areas.5, 6, 7
Based on literature review, this is the first case of A. lusatiense causing endophthalmitis as well as human disease. PubMed and Cochrane Library databases were searched on June 20, 2020 using the following terms: Aquamicrobium, Defluvibacter, and endophthalmitis. Literature review did not reveal reports of infection caused by this species. However, Venkat et al. recently described a case of postoperative endophthalmitis secondary to another organism within the same genus, A. terrae, representing the only other human infection secondary to Aquamicrobium spp.8 This case also presented as hypopyon uveitis with large, pigmented keratic precipitates.
There is no consensus for the management of chronic bacterial endophthalmitis. There are reports of successful treatment with nonsurgical therapy; however, in cases with persistent inflammation after intravitreal antibiotic injection, bacteria have been shown to remain on explanted lenses on electron microscopy, and intraocular lens explantation with removal of the entire capsular bag complex can be curative.9 Case series on patients with P. acnes endophthalmitis also support a role for intraocular lens explantation.10,11 Based on these reports and the severity of the infection in the present case, we elected for surgical removal of the intraocular lens implant and 6 months of antibiotic treatment with an excellent outcome.
4 Conclusion
To our knowledge, this is the first report of A. lusatiense causing endophthalmitis after cataract surgery. Our patient responded completely to broad-spectrum intravitreal antimicrobial therapy along with intraocular lens explantation and adjunct oral quinolones. Greater awareness of this previously unreported causative organism of endophthalmitis may assist in the diagnosis and management of future cases.
Patient consent statement
Consent has been obtained from the patient.
Funding
Supported in part by a VitreoRetinal Surgery Foundation Research Award and a 10.13039/100001818 Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organizations had no role in the design or conduct of this research.
Authorship
All authors attest that they met the current ICMJE criteria.
Declaration of competing interest
The authors declare that there are no conflicts of interest related to this manuscript. | ADALIMUMAB, METHOTREXATE, PREDNISONE | DrugsGivenReaction | CC BY-NC-ND | 33732953 | 19,407,694 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vitritis'. | Chronic endophthalmitis from Aquamicrobium lusatiense.
To report a case of chronic endophthalmitis caused by Aquamicrobium lusatiense following phacoemulsification surgery.
A 71 year-old woman was referred for chronic ocular inflammation after cataract surgery. Serologic testing was negative for common infectious etiologies. Her condition deteriorated on immune-modulating therapy prompting vitreous biopsy, which confirmed infection with A. lusatiense. She was managed successfully with intravitreal antibiotic pharmacotherapy and intraocular lens explantation.
This is the first reported case of A. lusatiense causing endophthalmitis, or disease in a human, in the literature.
1 Introduction
Chronic postoperative endophthalmitis is a vision-threatening complication of ophthalmic surgery that can be caused by a range of organisms, from Propionibacterium acnes, to Staphylococcus epidermidis, to other atypical bacteria and select fungal species.1,2 These cases often pose a diagnostic challenge, typically presenting with smoldering inflammation, which can respond initially to corticosteroid therapy. Herein we describe the first case of Aquamicrobium lusatiense causing endophthalmitis, or indeed, disease in a human, in the English language literature.
2 Case report
A 71 year-old immunocompetent Caucasian woman underwent uncomplicated phacoemulsification surgery with an outside provider. Immediately following surgery, Snellen visual acuity was measured at 20/20. At the one-month post-operative visit, anterior chamber cell was noted, and she was treated with topical 0.1% preservative-free dexamethasone due to a self-reported allergy to 1% prednisolone acetate. After completing a taper, she presented with rebound inflammation and was treated with twice daily 0.05% difluprednate for three days before transitioning back to 0.1% dexamethasone, remaining on twice daily dosing for maintenance. At her six-month follow-up visit she underwent yttrium-aluminum-garnet (YAG) laser posterior capsulotomy without complication. Sixteen months after cataract surgery, she transferred care to a new provider who tapered her off dexamethasone drops. She returned one month later with acute-onset unilateral hypopyon uveitis with a visual acuity of 20/400 and was initiated on topical 0.05% difluprednate every 2 hours and referred for evaluation to the retina service at Vanderbilt Eye Institute.
Initial examination showed mild corneal edema with diffuse, pigmented keratic precipitates and 3+ anterior chamber cell in the right eye. The vitreous was clear and there was no macular edema on optical coherence tomography (OCT). Serologic testing for treponemal IgG, herpes simplex virus (HSV) type 1 and 2 IgM, quantiferon gold, and Lyme ELISA were negative. Chest radiography was normal. Due to the corneal edema and pigmented keratic precipitates, herpetic etiology remained high on the differential. Therefore, empiric oral valacyclovir was started and difluprednate slowly tapered. One month later she returned with 20/60 visual acuity. The anterior chamber was quiet, and she transitioned to 0.1% fluorometholone taper. She returned two months later with stable exam findings but reported that she had flared twice and resumed difluprednate after consultation with an outside provider. Oral prednisone and 15 mg weekly methotrexate were started. Her disease quieted and vision improved to 20/50, but two months after initiation of methotrexate visual acuity deteriorated to 20/150, and examination showed 1+ anterior chamber cell and 2+ vitreous cell. Methotrexate was increased to 25 mg weekly. One month later, her vision improved to 20/70, but she remained active, with 2+ anterior chamber and vitreous cell, and was started on adalimumab 40mg every other week.
Following initiation of adalimumab, her visual acuity deteriorated to count fingers. Slit lamp examination showed increase in keratic precipitates (Fig. 1A) with a hazy view of the anterior and posterior chambers. B-scan ultrasonography demonstrated hyperechoic vitreous opacities concerning for vitritis (Fig. 1B). Her inflammation continued to worsen despite immunosuppression, and a diagnostic vitrectomy was performed.Fig. 1 (A) Slit-lamp photograph of the right eye during demonstrating diffuse pigmented keratic precipitates and hazy anterior chamber. (B) B-scan ultrasonography, transverse scan at 3 o'clock demonstrating posterior vitreous detachment with hyperechoic vitreous opacities.
Fig. 1
Intraoperatively, polymerase chain reaction (PCR) testing of aqueous for HSV 1 and 2, varicella zoster virus, and cytomegalovirus was negative. Vitreous biopsy and biopsy of the posterior capsule were sent for microbiology and the patient was treated with 1mg intravitreal vancomycin due to suspicion for P. acnes endophthalmitis. Cultures from vitreous and posterior capsule demonstrated light growth of a Gram-negative rod that was sent to the Tennessee state laboratory for identification. The state laboratory identified the organism as A. lusatiense.
Immune modulating therapy was discontinued, and the patient underwent repeat vitrectomy with explantation of the intraocular lens as well as intravitreal injections of 2mg ceftazidine and 160μg moxifloxacin to cover the Gram negative organism. Additionally, she was treated with six months of oral ciprofloxacin 500mg daily. She continued to improve; two months after completion of her course of ciprofloxacin, the eye remained quiet and a scleral fixated intraocular lens was placed. One year after diagnostic vitrectomy at her most recent follow-up, the keratic precipitates, anterior chamber cell, and vitreous cell had resolved (Fig. 2), and best-corrected Snellen visual acuity was measured at 20/30–2.Fig. 2 Slit lamp photograph of the right eye after intraocular lens explantation and one month of oral ciprofloxacin showing complete resolution of pigmented keratic precipitates in a quiet eye.
Fig. 2
3 Discussion
A. lusatiense is an aerobic Gram-negative, catalase- and oxidase-positive rod. Formerly Defluvibacter lusatiensis, the species was first described in 1999 after isolation from waste water.3 The organism was transferred to the Aquamicrobium genus in 2009 due to genetic similarity to A. defluvii.4 While Aquamicrobium spp. are most commonly isolated from waste water, they have also been identified in contaminated soil and in tidal areas.5, 6, 7
Based on literature review, this is the first case of A. lusatiense causing endophthalmitis as well as human disease. PubMed and Cochrane Library databases were searched on June 20, 2020 using the following terms: Aquamicrobium, Defluvibacter, and endophthalmitis. Literature review did not reveal reports of infection caused by this species. However, Venkat et al. recently described a case of postoperative endophthalmitis secondary to another organism within the same genus, A. terrae, representing the only other human infection secondary to Aquamicrobium spp.8 This case also presented as hypopyon uveitis with large, pigmented keratic precipitates.
There is no consensus for the management of chronic bacterial endophthalmitis. There are reports of successful treatment with nonsurgical therapy; however, in cases with persistent inflammation after intravitreal antibiotic injection, bacteria have been shown to remain on explanted lenses on electron microscopy, and intraocular lens explantation with removal of the entire capsular bag complex can be curative.9 Case series on patients with P. acnes endophthalmitis also support a role for intraocular lens explantation.10,11 Based on these reports and the severity of the infection in the present case, we elected for surgical removal of the intraocular lens implant and 6 months of antibiotic treatment with an excellent outcome.
4 Conclusion
To our knowledge, this is the first report of A. lusatiense causing endophthalmitis after cataract surgery. Our patient responded completely to broad-spectrum intravitreal antimicrobial therapy along with intraocular lens explantation and adjunct oral quinolones. Greater awareness of this previously unreported causative organism of endophthalmitis may assist in the diagnosis and management of future cases.
Patient consent statement
Consent has been obtained from the patient.
Funding
Supported in part by a VitreoRetinal Surgery Foundation Research Award and a 10.13039/100001818 Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organizations had no role in the design or conduct of this research.
Authorship
All authors attest that they met the current ICMJE criteria.
Declaration of competing interest
The authors declare that there are no conflicts of interest related to this manuscript. | ADALIMUMAB, METHOTREXATE, PREDNISONE | DrugsGivenReaction | CC BY-NC-ND | 33732953 | 19,407,694 | 2021-06 |
What was the administration route of drug 'ADALIMUMAB'? | Chronic endophthalmitis from Aquamicrobium lusatiense.
To report a case of chronic endophthalmitis caused by Aquamicrobium lusatiense following phacoemulsification surgery.
A 71 year-old woman was referred for chronic ocular inflammation after cataract surgery. Serologic testing was negative for common infectious etiologies. Her condition deteriorated on immune-modulating therapy prompting vitreous biopsy, which confirmed infection with A. lusatiense. She was managed successfully with intravitreal antibiotic pharmacotherapy and intraocular lens explantation.
This is the first reported case of A. lusatiense causing endophthalmitis, or disease in a human, in the literature.
1 Introduction
Chronic postoperative endophthalmitis is a vision-threatening complication of ophthalmic surgery that can be caused by a range of organisms, from Propionibacterium acnes, to Staphylococcus epidermidis, to other atypical bacteria and select fungal species.1,2 These cases often pose a diagnostic challenge, typically presenting with smoldering inflammation, which can respond initially to corticosteroid therapy. Herein we describe the first case of Aquamicrobium lusatiense causing endophthalmitis, or indeed, disease in a human, in the English language literature.
2 Case report
A 71 year-old immunocompetent Caucasian woman underwent uncomplicated phacoemulsification surgery with an outside provider. Immediately following surgery, Snellen visual acuity was measured at 20/20. At the one-month post-operative visit, anterior chamber cell was noted, and she was treated with topical 0.1% preservative-free dexamethasone due to a self-reported allergy to 1% prednisolone acetate. After completing a taper, she presented with rebound inflammation and was treated with twice daily 0.05% difluprednate for three days before transitioning back to 0.1% dexamethasone, remaining on twice daily dosing for maintenance. At her six-month follow-up visit she underwent yttrium-aluminum-garnet (YAG) laser posterior capsulotomy without complication. Sixteen months after cataract surgery, she transferred care to a new provider who tapered her off dexamethasone drops. She returned one month later with acute-onset unilateral hypopyon uveitis with a visual acuity of 20/400 and was initiated on topical 0.05% difluprednate every 2 hours and referred for evaluation to the retina service at Vanderbilt Eye Institute.
Initial examination showed mild corneal edema with diffuse, pigmented keratic precipitates and 3+ anterior chamber cell in the right eye. The vitreous was clear and there was no macular edema on optical coherence tomography (OCT). Serologic testing for treponemal IgG, herpes simplex virus (HSV) type 1 and 2 IgM, quantiferon gold, and Lyme ELISA were negative. Chest radiography was normal. Due to the corneal edema and pigmented keratic precipitates, herpetic etiology remained high on the differential. Therefore, empiric oral valacyclovir was started and difluprednate slowly tapered. One month later she returned with 20/60 visual acuity. The anterior chamber was quiet, and she transitioned to 0.1% fluorometholone taper. She returned two months later with stable exam findings but reported that she had flared twice and resumed difluprednate after consultation with an outside provider. Oral prednisone and 15 mg weekly methotrexate were started. Her disease quieted and vision improved to 20/50, but two months after initiation of methotrexate visual acuity deteriorated to 20/150, and examination showed 1+ anterior chamber cell and 2+ vitreous cell. Methotrexate was increased to 25 mg weekly. One month later, her vision improved to 20/70, but she remained active, with 2+ anterior chamber and vitreous cell, and was started on adalimumab 40mg every other week.
Following initiation of adalimumab, her visual acuity deteriorated to count fingers. Slit lamp examination showed increase in keratic precipitates (Fig. 1A) with a hazy view of the anterior and posterior chambers. B-scan ultrasonography demonstrated hyperechoic vitreous opacities concerning for vitritis (Fig. 1B). Her inflammation continued to worsen despite immunosuppression, and a diagnostic vitrectomy was performed.Fig. 1 (A) Slit-lamp photograph of the right eye during demonstrating diffuse pigmented keratic precipitates and hazy anterior chamber. (B) B-scan ultrasonography, transverse scan at 3 o'clock demonstrating posterior vitreous detachment with hyperechoic vitreous opacities.
Fig. 1
Intraoperatively, polymerase chain reaction (PCR) testing of aqueous for HSV 1 and 2, varicella zoster virus, and cytomegalovirus was negative. Vitreous biopsy and biopsy of the posterior capsule were sent for microbiology and the patient was treated with 1mg intravitreal vancomycin due to suspicion for P. acnes endophthalmitis. Cultures from vitreous and posterior capsule demonstrated light growth of a Gram-negative rod that was sent to the Tennessee state laboratory for identification. The state laboratory identified the organism as A. lusatiense.
Immune modulating therapy was discontinued, and the patient underwent repeat vitrectomy with explantation of the intraocular lens as well as intravitreal injections of 2mg ceftazidine and 160μg moxifloxacin to cover the Gram negative organism. Additionally, she was treated with six months of oral ciprofloxacin 500mg daily. She continued to improve; two months after completion of her course of ciprofloxacin, the eye remained quiet and a scleral fixated intraocular lens was placed. One year after diagnostic vitrectomy at her most recent follow-up, the keratic precipitates, anterior chamber cell, and vitreous cell had resolved (Fig. 2), and best-corrected Snellen visual acuity was measured at 20/30–2.Fig. 2 Slit lamp photograph of the right eye after intraocular lens explantation and one month of oral ciprofloxacin showing complete resolution of pigmented keratic precipitates in a quiet eye.
Fig. 2
3 Discussion
A. lusatiense is an aerobic Gram-negative, catalase- and oxidase-positive rod. Formerly Defluvibacter lusatiensis, the species was first described in 1999 after isolation from waste water.3 The organism was transferred to the Aquamicrobium genus in 2009 due to genetic similarity to A. defluvii.4 While Aquamicrobium spp. are most commonly isolated from waste water, they have also been identified in contaminated soil and in tidal areas.5, 6, 7
Based on literature review, this is the first case of A. lusatiense causing endophthalmitis as well as human disease. PubMed and Cochrane Library databases were searched on June 20, 2020 using the following terms: Aquamicrobium, Defluvibacter, and endophthalmitis. Literature review did not reveal reports of infection caused by this species. However, Venkat et al. recently described a case of postoperative endophthalmitis secondary to another organism within the same genus, A. terrae, representing the only other human infection secondary to Aquamicrobium spp.8 This case also presented as hypopyon uveitis with large, pigmented keratic precipitates.
There is no consensus for the management of chronic bacterial endophthalmitis. There are reports of successful treatment with nonsurgical therapy; however, in cases with persistent inflammation after intravitreal antibiotic injection, bacteria have been shown to remain on explanted lenses on electron microscopy, and intraocular lens explantation with removal of the entire capsular bag complex can be curative.9 Case series on patients with P. acnes endophthalmitis also support a role for intraocular lens explantation.10,11 Based on these reports and the severity of the infection in the present case, we elected for surgical removal of the intraocular lens implant and 6 months of antibiotic treatment with an excellent outcome.
4 Conclusion
To our knowledge, this is the first report of A. lusatiense causing endophthalmitis after cataract surgery. Our patient responded completely to broad-spectrum intravitreal antimicrobial therapy along with intraocular lens explantation and adjunct oral quinolones. Greater awareness of this previously unreported causative organism of endophthalmitis may assist in the diagnosis and management of future cases.
Patient consent statement
Consent has been obtained from the patient.
Funding
Supported in part by a VitreoRetinal Surgery Foundation Research Award and a 10.13039/100001818 Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organizations had no role in the design or conduct of this research.
Authorship
All authors attest that they met the current ICMJE criteria.
Declaration of competing interest
The authors declare that there are no conflicts of interest related to this manuscript. | Subcutaneous | DrugAdministrationRoute | CC BY-NC-ND | 33732953 | 19,407,694 | 2021-06 |
What was the administration route of drug 'PREDNISONE'? | Chronic endophthalmitis from Aquamicrobium lusatiense.
To report a case of chronic endophthalmitis caused by Aquamicrobium lusatiense following phacoemulsification surgery.
A 71 year-old woman was referred for chronic ocular inflammation after cataract surgery. Serologic testing was negative for common infectious etiologies. Her condition deteriorated on immune-modulating therapy prompting vitreous biopsy, which confirmed infection with A. lusatiense. She was managed successfully with intravitreal antibiotic pharmacotherapy and intraocular lens explantation.
This is the first reported case of A. lusatiense causing endophthalmitis, or disease in a human, in the literature.
1 Introduction
Chronic postoperative endophthalmitis is a vision-threatening complication of ophthalmic surgery that can be caused by a range of organisms, from Propionibacterium acnes, to Staphylococcus epidermidis, to other atypical bacteria and select fungal species.1,2 These cases often pose a diagnostic challenge, typically presenting with smoldering inflammation, which can respond initially to corticosteroid therapy. Herein we describe the first case of Aquamicrobium lusatiense causing endophthalmitis, or indeed, disease in a human, in the English language literature.
2 Case report
A 71 year-old immunocompetent Caucasian woman underwent uncomplicated phacoemulsification surgery with an outside provider. Immediately following surgery, Snellen visual acuity was measured at 20/20. At the one-month post-operative visit, anterior chamber cell was noted, and she was treated with topical 0.1% preservative-free dexamethasone due to a self-reported allergy to 1% prednisolone acetate. After completing a taper, she presented with rebound inflammation and was treated with twice daily 0.05% difluprednate for three days before transitioning back to 0.1% dexamethasone, remaining on twice daily dosing for maintenance. At her six-month follow-up visit she underwent yttrium-aluminum-garnet (YAG) laser posterior capsulotomy without complication. Sixteen months after cataract surgery, she transferred care to a new provider who tapered her off dexamethasone drops. She returned one month later with acute-onset unilateral hypopyon uveitis with a visual acuity of 20/400 and was initiated on topical 0.05% difluprednate every 2 hours and referred for evaluation to the retina service at Vanderbilt Eye Institute.
Initial examination showed mild corneal edema with diffuse, pigmented keratic precipitates and 3+ anterior chamber cell in the right eye. The vitreous was clear and there was no macular edema on optical coherence tomography (OCT). Serologic testing for treponemal IgG, herpes simplex virus (HSV) type 1 and 2 IgM, quantiferon gold, and Lyme ELISA were negative. Chest radiography was normal. Due to the corneal edema and pigmented keratic precipitates, herpetic etiology remained high on the differential. Therefore, empiric oral valacyclovir was started and difluprednate slowly tapered. One month later she returned with 20/60 visual acuity. The anterior chamber was quiet, and she transitioned to 0.1% fluorometholone taper. She returned two months later with stable exam findings but reported that she had flared twice and resumed difluprednate after consultation with an outside provider. Oral prednisone and 15 mg weekly methotrexate were started. Her disease quieted and vision improved to 20/50, but two months after initiation of methotrexate visual acuity deteriorated to 20/150, and examination showed 1+ anterior chamber cell and 2+ vitreous cell. Methotrexate was increased to 25 mg weekly. One month later, her vision improved to 20/70, but she remained active, with 2+ anterior chamber and vitreous cell, and was started on adalimumab 40mg every other week.
Following initiation of adalimumab, her visual acuity deteriorated to count fingers. Slit lamp examination showed increase in keratic precipitates (Fig. 1A) with a hazy view of the anterior and posterior chambers. B-scan ultrasonography demonstrated hyperechoic vitreous opacities concerning for vitritis (Fig. 1B). Her inflammation continued to worsen despite immunosuppression, and a diagnostic vitrectomy was performed.Fig. 1 (A) Slit-lamp photograph of the right eye during demonstrating diffuse pigmented keratic precipitates and hazy anterior chamber. (B) B-scan ultrasonography, transverse scan at 3 o'clock demonstrating posterior vitreous detachment with hyperechoic vitreous opacities.
Fig. 1
Intraoperatively, polymerase chain reaction (PCR) testing of aqueous for HSV 1 and 2, varicella zoster virus, and cytomegalovirus was negative. Vitreous biopsy and biopsy of the posterior capsule were sent for microbiology and the patient was treated with 1mg intravitreal vancomycin due to suspicion for P. acnes endophthalmitis. Cultures from vitreous and posterior capsule demonstrated light growth of a Gram-negative rod that was sent to the Tennessee state laboratory for identification. The state laboratory identified the organism as A. lusatiense.
Immune modulating therapy was discontinued, and the patient underwent repeat vitrectomy with explantation of the intraocular lens as well as intravitreal injections of 2mg ceftazidine and 160μg moxifloxacin to cover the Gram negative organism. Additionally, she was treated with six months of oral ciprofloxacin 500mg daily. She continued to improve; two months after completion of her course of ciprofloxacin, the eye remained quiet and a scleral fixated intraocular lens was placed. One year after diagnostic vitrectomy at her most recent follow-up, the keratic precipitates, anterior chamber cell, and vitreous cell had resolved (Fig. 2), and best-corrected Snellen visual acuity was measured at 20/30–2.Fig. 2 Slit lamp photograph of the right eye after intraocular lens explantation and one month of oral ciprofloxacin showing complete resolution of pigmented keratic precipitates in a quiet eye.
Fig. 2
3 Discussion
A. lusatiense is an aerobic Gram-negative, catalase- and oxidase-positive rod. Formerly Defluvibacter lusatiensis, the species was first described in 1999 after isolation from waste water.3 The organism was transferred to the Aquamicrobium genus in 2009 due to genetic similarity to A. defluvii.4 While Aquamicrobium spp. are most commonly isolated from waste water, they have also been identified in contaminated soil and in tidal areas.5, 6, 7
Based on literature review, this is the first case of A. lusatiense causing endophthalmitis as well as human disease. PubMed and Cochrane Library databases were searched on June 20, 2020 using the following terms: Aquamicrobium, Defluvibacter, and endophthalmitis. Literature review did not reveal reports of infection caused by this species. However, Venkat et al. recently described a case of postoperative endophthalmitis secondary to another organism within the same genus, A. terrae, representing the only other human infection secondary to Aquamicrobium spp.8 This case also presented as hypopyon uveitis with large, pigmented keratic precipitates.
There is no consensus for the management of chronic bacterial endophthalmitis. There are reports of successful treatment with nonsurgical therapy; however, in cases with persistent inflammation after intravitreal antibiotic injection, bacteria have been shown to remain on explanted lenses on electron microscopy, and intraocular lens explantation with removal of the entire capsular bag complex can be curative.9 Case series on patients with P. acnes endophthalmitis also support a role for intraocular lens explantation.10,11 Based on these reports and the severity of the infection in the present case, we elected for surgical removal of the intraocular lens implant and 6 months of antibiotic treatment with an excellent outcome.
4 Conclusion
To our knowledge, this is the first report of A. lusatiense causing endophthalmitis after cataract surgery. Our patient responded completely to broad-spectrum intravitreal antimicrobial therapy along with intraocular lens explantation and adjunct oral quinolones. Greater awareness of this previously unreported causative organism of endophthalmitis may assist in the diagnosis and management of future cases.
Patient consent statement
Consent has been obtained from the patient.
Funding
Supported in part by a VitreoRetinal Surgery Foundation Research Award and a 10.13039/100001818 Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organizations had no role in the design or conduct of this research.
Authorship
All authors attest that they met the current ICMJE criteria.
Declaration of competing interest
The authors declare that there are no conflicts of interest related to this manuscript. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33732953 | 19,407,694 | 2021-06 |
What was the dosage of drug 'ADALIMUMAB'? | Chronic endophthalmitis from Aquamicrobium lusatiense.
To report a case of chronic endophthalmitis caused by Aquamicrobium lusatiense following phacoemulsification surgery.
A 71 year-old woman was referred for chronic ocular inflammation after cataract surgery. Serologic testing was negative for common infectious etiologies. Her condition deteriorated on immune-modulating therapy prompting vitreous biopsy, which confirmed infection with A. lusatiense. She was managed successfully with intravitreal antibiotic pharmacotherapy and intraocular lens explantation.
This is the first reported case of A. lusatiense causing endophthalmitis, or disease in a human, in the literature.
1 Introduction
Chronic postoperative endophthalmitis is a vision-threatening complication of ophthalmic surgery that can be caused by a range of organisms, from Propionibacterium acnes, to Staphylococcus epidermidis, to other atypical bacteria and select fungal species.1,2 These cases often pose a diagnostic challenge, typically presenting with smoldering inflammation, which can respond initially to corticosteroid therapy. Herein we describe the first case of Aquamicrobium lusatiense causing endophthalmitis, or indeed, disease in a human, in the English language literature.
2 Case report
A 71 year-old immunocompetent Caucasian woman underwent uncomplicated phacoemulsification surgery with an outside provider. Immediately following surgery, Snellen visual acuity was measured at 20/20. At the one-month post-operative visit, anterior chamber cell was noted, and she was treated with topical 0.1% preservative-free dexamethasone due to a self-reported allergy to 1% prednisolone acetate. After completing a taper, she presented with rebound inflammation and was treated with twice daily 0.05% difluprednate for three days before transitioning back to 0.1% dexamethasone, remaining on twice daily dosing for maintenance. At her six-month follow-up visit she underwent yttrium-aluminum-garnet (YAG) laser posterior capsulotomy without complication. Sixteen months after cataract surgery, she transferred care to a new provider who tapered her off dexamethasone drops. She returned one month later with acute-onset unilateral hypopyon uveitis with a visual acuity of 20/400 and was initiated on topical 0.05% difluprednate every 2 hours and referred for evaluation to the retina service at Vanderbilt Eye Institute.
Initial examination showed mild corneal edema with diffuse, pigmented keratic precipitates and 3+ anterior chamber cell in the right eye. The vitreous was clear and there was no macular edema on optical coherence tomography (OCT). Serologic testing for treponemal IgG, herpes simplex virus (HSV) type 1 and 2 IgM, quantiferon gold, and Lyme ELISA were negative. Chest radiography was normal. Due to the corneal edema and pigmented keratic precipitates, herpetic etiology remained high on the differential. Therefore, empiric oral valacyclovir was started and difluprednate slowly tapered. One month later she returned with 20/60 visual acuity. The anterior chamber was quiet, and she transitioned to 0.1% fluorometholone taper. She returned two months later with stable exam findings but reported that she had flared twice and resumed difluprednate after consultation with an outside provider. Oral prednisone and 15 mg weekly methotrexate were started. Her disease quieted and vision improved to 20/50, but two months after initiation of methotrexate visual acuity deteriorated to 20/150, and examination showed 1+ anterior chamber cell and 2+ vitreous cell. Methotrexate was increased to 25 mg weekly. One month later, her vision improved to 20/70, but she remained active, with 2+ anterior chamber and vitreous cell, and was started on adalimumab 40mg every other week.
Following initiation of adalimumab, her visual acuity deteriorated to count fingers. Slit lamp examination showed increase in keratic precipitates (Fig. 1A) with a hazy view of the anterior and posterior chambers. B-scan ultrasonography demonstrated hyperechoic vitreous opacities concerning for vitritis (Fig. 1B). Her inflammation continued to worsen despite immunosuppression, and a diagnostic vitrectomy was performed.Fig. 1 (A) Slit-lamp photograph of the right eye during demonstrating diffuse pigmented keratic precipitates and hazy anterior chamber. (B) B-scan ultrasonography, transverse scan at 3 o'clock demonstrating posterior vitreous detachment with hyperechoic vitreous opacities.
Fig. 1
Intraoperatively, polymerase chain reaction (PCR) testing of aqueous for HSV 1 and 2, varicella zoster virus, and cytomegalovirus was negative. Vitreous biopsy and biopsy of the posterior capsule were sent for microbiology and the patient was treated with 1mg intravitreal vancomycin due to suspicion for P. acnes endophthalmitis. Cultures from vitreous and posterior capsule demonstrated light growth of a Gram-negative rod that was sent to the Tennessee state laboratory for identification. The state laboratory identified the organism as A. lusatiense.
Immune modulating therapy was discontinued, and the patient underwent repeat vitrectomy with explantation of the intraocular lens as well as intravitreal injections of 2mg ceftazidine and 160μg moxifloxacin to cover the Gram negative organism. Additionally, she was treated with six months of oral ciprofloxacin 500mg daily. She continued to improve; two months after completion of her course of ciprofloxacin, the eye remained quiet and a scleral fixated intraocular lens was placed. One year after diagnostic vitrectomy at her most recent follow-up, the keratic precipitates, anterior chamber cell, and vitreous cell had resolved (Fig. 2), and best-corrected Snellen visual acuity was measured at 20/30–2.Fig. 2 Slit lamp photograph of the right eye after intraocular lens explantation and one month of oral ciprofloxacin showing complete resolution of pigmented keratic precipitates in a quiet eye.
Fig. 2
3 Discussion
A. lusatiense is an aerobic Gram-negative, catalase- and oxidase-positive rod. Formerly Defluvibacter lusatiensis, the species was first described in 1999 after isolation from waste water.3 The organism was transferred to the Aquamicrobium genus in 2009 due to genetic similarity to A. defluvii.4 While Aquamicrobium spp. are most commonly isolated from waste water, they have also been identified in contaminated soil and in tidal areas.5, 6, 7
Based on literature review, this is the first case of A. lusatiense causing endophthalmitis as well as human disease. PubMed and Cochrane Library databases were searched on June 20, 2020 using the following terms: Aquamicrobium, Defluvibacter, and endophthalmitis. Literature review did not reveal reports of infection caused by this species. However, Venkat et al. recently described a case of postoperative endophthalmitis secondary to another organism within the same genus, A. terrae, representing the only other human infection secondary to Aquamicrobium spp.8 This case also presented as hypopyon uveitis with large, pigmented keratic precipitates.
There is no consensus for the management of chronic bacterial endophthalmitis. There are reports of successful treatment with nonsurgical therapy; however, in cases with persistent inflammation after intravitreal antibiotic injection, bacteria have been shown to remain on explanted lenses on electron microscopy, and intraocular lens explantation with removal of the entire capsular bag complex can be curative.9 Case series on patients with P. acnes endophthalmitis also support a role for intraocular lens explantation.10,11 Based on these reports and the severity of the infection in the present case, we elected for surgical removal of the intraocular lens implant and 6 months of antibiotic treatment with an excellent outcome.
4 Conclusion
To our knowledge, this is the first report of A. lusatiense causing endophthalmitis after cataract surgery. Our patient responded completely to broad-spectrum intravitreal antimicrobial therapy along with intraocular lens explantation and adjunct oral quinolones. Greater awareness of this previously unreported causative organism of endophthalmitis may assist in the diagnosis and management of future cases.
Patient consent statement
Consent has been obtained from the patient.
Funding
Supported in part by a VitreoRetinal Surgery Foundation Research Award and a 10.13039/100001818 Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organizations had no role in the design or conduct of this research.
Authorship
All authors attest that they met the current ICMJE criteria.
Declaration of competing interest
The authors declare that there are no conflicts of interest related to this manuscript. | 40 mg (milligrams). | DrugDosage | CC BY-NC-ND | 33732953 | 19,407,694 | 2021-06 |
What was the outcome of reaction 'Drug ineffective'? | Chronic endophthalmitis from Aquamicrobium lusatiense.
To report a case of chronic endophthalmitis caused by Aquamicrobium lusatiense following phacoemulsification surgery.
A 71 year-old woman was referred for chronic ocular inflammation after cataract surgery. Serologic testing was negative for common infectious etiologies. Her condition deteriorated on immune-modulating therapy prompting vitreous biopsy, which confirmed infection with A. lusatiense. She was managed successfully with intravitreal antibiotic pharmacotherapy and intraocular lens explantation.
This is the first reported case of A. lusatiense causing endophthalmitis, or disease in a human, in the literature.
1 Introduction
Chronic postoperative endophthalmitis is a vision-threatening complication of ophthalmic surgery that can be caused by a range of organisms, from Propionibacterium acnes, to Staphylococcus epidermidis, to other atypical bacteria and select fungal species.1,2 These cases often pose a diagnostic challenge, typically presenting with smoldering inflammation, which can respond initially to corticosteroid therapy. Herein we describe the first case of Aquamicrobium lusatiense causing endophthalmitis, or indeed, disease in a human, in the English language literature.
2 Case report
A 71 year-old immunocompetent Caucasian woman underwent uncomplicated phacoemulsification surgery with an outside provider. Immediately following surgery, Snellen visual acuity was measured at 20/20. At the one-month post-operative visit, anterior chamber cell was noted, and she was treated with topical 0.1% preservative-free dexamethasone due to a self-reported allergy to 1% prednisolone acetate. After completing a taper, she presented with rebound inflammation and was treated with twice daily 0.05% difluprednate for three days before transitioning back to 0.1% dexamethasone, remaining on twice daily dosing for maintenance. At her six-month follow-up visit she underwent yttrium-aluminum-garnet (YAG) laser posterior capsulotomy without complication. Sixteen months after cataract surgery, she transferred care to a new provider who tapered her off dexamethasone drops. She returned one month later with acute-onset unilateral hypopyon uveitis with a visual acuity of 20/400 and was initiated on topical 0.05% difluprednate every 2 hours and referred for evaluation to the retina service at Vanderbilt Eye Institute.
Initial examination showed mild corneal edema with diffuse, pigmented keratic precipitates and 3+ anterior chamber cell in the right eye. The vitreous was clear and there was no macular edema on optical coherence tomography (OCT). Serologic testing for treponemal IgG, herpes simplex virus (HSV) type 1 and 2 IgM, quantiferon gold, and Lyme ELISA were negative. Chest radiography was normal. Due to the corneal edema and pigmented keratic precipitates, herpetic etiology remained high on the differential. Therefore, empiric oral valacyclovir was started and difluprednate slowly tapered. One month later she returned with 20/60 visual acuity. The anterior chamber was quiet, and she transitioned to 0.1% fluorometholone taper. She returned two months later with stable exam findings but reported that she had flared twice and resumed difluprednate after consultation with an outside provider. Oral prednisone and 15 mg weekly methotrexate were started. Her disease quieted and vision improved to 20/50, but two months after initiation of methotrexate visual acuity deteriorated to 20/150, and examination showed 1+ anterior chamber cell and 2+ vitreous cell. Methotrexate was increased to 25 mg weekly. One month later, her vision improved to 20/70, but she remained active, with 2+ anterior chamber and vitreous cell, and was started on adalimumab 40mg every other week.
Following initiation of adalimumab, her visual acuity deteriorated to count fingers. Slit lamp examination showed increase in keratic precipitates (Fig. 1A) with a hazy view of the anterior and posterior chambers. B-scan ultrasonography demonstrated hyperechoic vitreous opacities concerning for vitritis (Fig. 1B). Her inflammation continued to worsen despite immunosuppression, and a diagnostic vitrectomy was performed.Fig. 1 (A) Slit-lamp photograph of the right eye during demonstrating diffuse pigmented keratic precipitates and hazy anterior chamber. (B) B-scan ultrasonography, transverse scan at 3 o'clock demonstrating posterior vitreous detachment with hyperechoic vitreous opacities.
Fig. 1
Intraoperatively, polymerase chain reaction (PCR) testing of aqueous for HSV 1 and 2, varicella zoster virus, and cytomegalovirus was negative. Vitreous biopsy and biopsy of the posterior capsule were sent for microbiology and the patient was treated with 1mg intravitreal vancomycin due to suspicion for P. acnes endophthalmitis. Cultures from vitreous and posterior capsule demonstrated light growth of a Gram-negative rod that was sent to the Tennessee state laboratory for identification. The state laboratory identified the organism as A. lusatiense.
Immune modulating therapy was discontinued, and the patient underwent repeat vitrectomy with explantation of the intraocular lens as well as intravitreal injections of 2mg ceftazidine and 160μg moxifloxacin to cover the Gram negative organism. Additionally, she was treated with six months of oral ciprofloxacin 500mg daily. She continued to improve; two months after completion of her course of ciprofloxacin, the eye remained quiet and a scleral fixated intraocular lens was placed. One year after diagnostic vitrectomy at her most recent follow-up, the keratic precipitates, anterior chamber cell, and vitreous cell had resolved (Fig. 2), and best-corrected Snellen visual acuity was measured at 20/30–2.Fig. 2 Slit lamp photograph of the right eye after intraocular lens explantation and one month of oral ciprofloxacin showing complete resolution of pigmented keratic precipitates in a quiet eye.
Fig. 2
3 Discussion
A. lusatiense is an aerobic Gram-negative, catalase- and oxidase-positive rod. Formerly Defluvibacter lusatiensis, the species was first described in 1999 after isolation from waste water.3 The organism was transferred to the Aquamicrobium genus in 2009 due to genetic similarity to A. defluvii.4 While Aquamicrobium spp. are most commonly isolated from waste water, they have also been identified in contaminated soil and in tidal areas.5, 6, 7
Based on literature review, this is the first case of A. lusatiense causing endophthalmitis as well as human disease. PubMed and Cochrane Library databases were searched on June 20, 2020 using the following terms: Aquamicrobium, Defluvibacter, and endophthalmitis. Literature review did not reveal reports of infection caused by this species. However, Venkat et al. recently described a case of postoperative endophthalmitis secondary to another organism within the same genus, A. terrae, representing the only other human infection secondary to Aquamicrobium spp.8 This case also presented as hypopyon uveitis with large, pigmented keratic precipitates.
There is no consensus for the management of chronic bacterial endophthalmitis. There are reports of successful treatment with nonsurgical therapy; however, in cases with persistent inflammation after intravitreal antibiotic injection, bacteria have been shown to remain on explanted lenses on electron microscopy, and intraocular lens explantation with removal of the entire capsular bag complex can be curative.9 Case series on patients with P. acnes endophthalmitis also support a role for intraocular lens explantation.10,11 Based on these reports and the severity of the infection in the present case, we elected for surgical removal of the intraocular lens implant and 6 months of antibiotic treatment with an excellent outcome.
4 Conclusion
To our knowledge, this is the first report of A. lusatiense causing endophthalmitis after cataract surgery. Our patient responded completely to broad-spectrum intravitreal antimicrobial therapy along with intraocular lens explantation and adjunct oral quinolones. Greater awareness of this previously unreported causative organism of endophthalmitis may assist in the diagnosis and management of future cases.
Patient consent statement
Consent has been obtained from the patient.
Funding
Supported in part by a VitreoRetinal Surgery Foundation Research Award and a 10.13039/100001818 Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organizations had no role in the design or conduct of this research.
Authorship
All authors attest that they met the current ICMJE criteria.
Declaration of competing interest
The authors declare that there are no conflicts of interest related to this manuscript. | Recovered | ReactionOutcome | CC BY-NC-ND | 33732953 | 19,407,694 | 2021-06 |
What was the outcome of reaction 'Vitritis'? | Chronic endophthalmitis from Aquamicrobium lusatiense.
To report a case of chronic endophthalmitis caused by Aquamicrobium lusatiense following phacoemulsification surgery.
A 71 year-old woman was referred for chronic ocular inflammation after cataract surgery. Serologic testing was negative for common infectious etiologies. Her condition deteriorated on immune-modulating therapy prompting vitreous biopsy, which confirmed infection with A. lusatiense. She was managed successfully with intravitreal antibiotic pharmacotherapy and intraocular lens explantation.
This is the first reported case of A. lusatiense causing endophthalmitis, or disease in a human, in the literature.
1 Introduction
Chronic postoperative endophthalmitis is a vision-threatening complication of ophthalmic surgery that can be caused by a range of organisms, from Propionibacterium acnes, to Staphylococcus epidermidis, to other atypical bacteria and select fungal species.1,2 These cases often pose a diagnostic challenge, typically presenting with smoldering inflammation, which can respond initially to corticosteroid therapy. Herein we describe the first case of Aquamicrobium lusatiense causing endophthalmitis, or indeed, disease in a human, in the English language literature.
2 Case report
A 71 year-old immunocompetent Caucasian woman underwent uncomplicated phacoemulsification surgery with an outside provider. Immediately following surgery, Snellen visual acuity was measured at 20/20. At the one-month post-operative visit, anterior chamber cell was noted, and she was treated with topical 0.1% preservative-free dexamethasone due to a self-reported allergy to 1% prednisolone acetate. After completing a taper, she presented with rebound inflammation and was treated with twice daily 0.05% difluprednate for three days before transitioning back to 0.1% dexamethasone, remaining on twice daily dosing for maintenance. At her six-month follow-up visit she underwent yttrium-aluminum-garnet (YAG) laser posterior capsulotomy without complication. Sixteen months after cataract surgery, she transferred care to a new provider who tapered her off dexamethasone drops. She returned one month later with acute-onset unilateral hypopyon uveitis with a visual acuity of 20/400 and was initiated on topical 0.05% difluprednate every 2 hours and referred for evaluation to the retina service at Vanderbilt Eye Institute.
Initial examination showed mild corneal edema with diffuse, pigmented keratic precipitates and 3+ anterior chamber cell in the right eye. The vitreous was clear and there was no macular edema on optical coherence tomography (OCT). Serologic testing for treponemal IgG, herpes simplex virus (HSV) type 1 and 2 IgM, quantiferon gold, and Lyme ELISA were negative. Chest radiography was normal. Due to the corneal edema and pigmented keratic precipitates, herpetic etiology remained high on the differential. Therefore, empiric oral valacyclovir was started and difluprednate slowly tapered. One month later she returned with 20/60 visual acuity. The anterior chamber was quiet, and she transitioned to 0.1% fluorometholone taper. She returned two months later with stable exam findings but reported that she had flared twice and resumed difluprednate after consultation with an outside provider. Oral prednisone and 15 mg weekly methotrexate were started. Her disease quieted and vision improved to 20/50, but two months after initiation of methotrexate visual acuity deteriorated to 20/150, and examination showed 1+ anterior chamber cell and 2+ vitreous cell. Methotrexate was increased to 25 mg weekly. One month later, her vision improved to 20/70, but she remained active, with 2+ anterior chamber and vitreous cell, and was started on adalimumab 40mg every other week.
Following initiation of adalimumab, her visual acuity deteriorated to count fingers. Slit lamp examination showed increase in keratic precipitates (Fig. 1A) with a hazy view of the anterior and posterior chambers. B-scan ultrasonography demonstrated hyperechoic vitreous opacities concerning for vitritis (Fig. 1B). Her inflammation continued to worsen despite immunosuppression, and a diagnostic vitrectomy was performed.Fig. 1 (A) Slit-lamp photograph of the right eye during demonstrating diffuse pigmented keratic precipitates and hazy anterior chamber. (B) B-scan ultrasonography, transverse scan at 3 o'clock demonstrating posterior vitreous detachment with hyperechoic vitreous opacities.
Fig. 1
Intraoperatively, polymerase chain reaction (PCR) testing of aqueous for HSV 1 and 2, varicella zoster virus, and cytomegalovirus was negative. Vitreous biopsy and biopsy of the posterior capsule were sent for microbiology and the patient was treated with 1mg intravitreal vancomycin due to suspicion for P. acnes endophthalmitis. Cultures from vitreous and posterior capsule demonstrated light growth of a Gram-negative rod that was sent to the Tennessee state laboratory for identification. The state laboratory identified the organism as A. lusatiense.
Immune modulating therapy was discontinued, and the patient underwent repeat vitrectomy with explantation of the intraocular lens as well as intravitreal injections of 2mg ceftazidine and 160μg moxifloxacin to cover the Gram negative organism. Additionally, she was treated with six months of oral ciprofloxacin 500mg daily. She continued to improve; two months after completion of her course of ciprofloxacin, the eye remained quiet and a scleral fixated intraocular lens was placed. One year after diagnostic vitrectomy at her most recent follow-up, the keratic precipitates, anterior chamber cell, and vitreous cell had resolved (Fig. 2), and best-corrected Snellen visual acuity was measured at 20/30–2.Fig. 2 Slit lamp photograph of the right eye after intraocular lens explantation and one month of oral ciprofloxacin showing complete resolution of pigmented keratic precipitates in a quiet eye.
Fig. 2
3 Discussion
A. lusatiense is an aerobic Gram-negative, catalase- and oxidase-positive rod. Formerly Defluvibacter lusatiensis, the species was first described in 1999 after isolation from waste water.3 The organism was transferred to the Aquamicrobium genus in 2009 due to genetic similarity to A. defluvii.4 While Aquamicrobium spp. are most commonly isolated from waste water, they have also been identified in contaminated soil and in tidal areas.5, 6, 7
Based on literature review, this is the first case of A. lusatiense causing endophthalmitis as well as human disease. PubMed and Cochrane Library databases were searched on June 20, 2020 using the following terms: Aquamicrobium, Defluvibacter, and endophthalmitis. Literature review did not reveal reports of infection caused by this species. However, Venkat et al. recently described a case of postoperative endophthalmitis secondary to another organism within the same genus, A. terrae, representing the only other human infection secondary to Aquamicrobium spp.8 This case also presented as hypopyon uveitis with large, pigmented keratic precipitates.
There is no consensus for the management of chronic bacterial endophthalmitis. There are reports of successful treatment with nonsurgical therapy; however, in cases with persistent inflammation after intravitreal antibiotic injection, bacteria have been shown to remain on explanted lenses on electron microscopy, and intraocular lens explantation with removal of the entire capsular bag complex can be curative.9 Case series on patients with P. acnes endophthalmitis also support a role for intraocular lens explantation.10,11 Based on these reports and the severity of the infection in the present case, we elected for surgical removal of the intraocular lens implant and 6 months of antibiotic treatment with an excellent outcome.
4 Conclusion
To our knowledge, this is the first report of A. lusatiense causing endophthalmitis after cataract surgery. Our patient responded completely to broad-spectrum intravitreal antimicrobial therapy along with intraocular lens explantation and adjunct oral quinolones. Greater awareness of this previously unreported causative organism of endophthalmitis may assist in the diagnosis and management of future cases.
Patient consent statement
Consent has been obtained from the patient.
Funding
Supported in part by a VitreoRetinal Surgery Foundation Research Award and a 10.13039/100001818 Research to Prevent Blindness unrestricted grant to the Vanderbilt Eye Institute. The sponsor or funding organizations had no role in the design or conduct of this research.
Authorship
All authors attest that they met the current ICMJE criteria.
Declaration of competing interest
The authors declare that there are no conflicts of interest related to this manuscript. | Recovered | ReactionOutcome | CC BY-NC-ND | 33732953 | 19,407,694 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis.
We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.
Introduction
Acute interstitial nephritis (AIN) is one of the common causes of acute kidney injury (AKI) and is associated with the presence of inflammatory infiltrates within the renal interstitium.1 AIN has been associated with 15% to 27% of patients with kidney dysfunction.1,2 However, the true incidence of AIN remains largely unrecognized as biopsy might not be sent in cases of clinical suspicion, and milder cases of AIN go undetected.1 There are many causes of AIN, with drug-induced AIN being the most common cause accounting for approximately 70% of all cases.3 Granulomatous interstitial nephritis (GIN) is a rare pathological feature seen in only 0.5% to 0.9% of all kidney biopsies.4 Although nitrofurantoin is a common cause of AIN, GIN is a rare entity. To our knowledge, there are only 2 case reports in the literature describing this condition.5,6 The knowledge of GIN is primarily based on case reports and case series. We present a case of a 71-year-old female with AKI found to have acute GIN on renal biopsy attributed to nitrofurantoin use.
Case Presentation
A 71-year-old female with a past medical history of multiple sclerosis and stress incontinence secondary to cystocele initially presented to her primary care physician with complaints of worsening lower extremity spasms and a new-onset visual hallucination. Routine basal metabolic panel performed for her symptoms incidentally revealed acute renal failure with a serum creatinine of 8.18 mg/dL. She was referred to the nearby hospital where she received 2-L boluses followed by maintenance intravenous fluids without significant improvement of kidney function. The patient was subsequently transferred to our institution for further workup and evaluation by nephrology. The patient’s baseline renal function was reportedly normal 3 months ago. She denied fever, chills, shortness of breath, skin rash, decreased urination, and other urinary symptoms on presentation. She was on long-term amantadine for fatigue related to multiple sclerosis. The patient used to follow-up with an urologist in Arizona for stress incontinence. She was scheduled to undergo an elective urological procedure for stress incontinence and was instructed to take nitrofurantoin 100 mg twice daily for 7 days before the procedure for presumed urinary tract infection (UTI). However, due to the coronavirus disease 2019 pandemic, her elective procedure was canceled, but she continued to take nitrofurantoin 100 mg twice daily for over 3 months for unknown reason. Clinical examination was remarkable for lethargy and altered mental status. Lungs were clear to auscultation bilaterally. The patient was afebrile, and vitals were within normal limits.
Laboratory workup confirmed AKI with a serum creatinine of 7.6 mg/dL and blood urea nitrogen of 60 mg/dL. Urine microscopy was bland without white blood cell, red blood cell, or protein, and urine cultures were negative for infection. Urine protein/creatinine ratio was 0.20 mg/mg. Liver function tests and serum albumin were within normal limits. Complete blood count demonstrated elevated absolute eosinophil count (1.8 × 103/µL). The serial laboratory tests and reference range are detailed in Table 1. Renal ultrasound was unremarkable with no evidence of renal calculi or hydronephrosis. Further workup including vasculitic screening, autoimmune panel, serum immunoglobulins, serum protein immunoelectrophoresis, complement level, hepatitis B and C, and parathyroid hormone level returned normal.
Table 1. Serial Laboratory Values.
Laboratory values (units) Day 1 Day 7 Day 14 Day 16 Reference ranges
Sodium (mmol/L) 140 139 143 144 136-145
Potassium (mmol/L) 4.5 4.0 3.5 3.8 3.4-5.1
Chloride (mmol/L) 108 101 101 106 98-107
Bicarbonate (mmol/L) 18 27 26 26 22-29
Blood urea nitrogen (mg/dL) 60 58 54 39 8-23
Creatinine (mg/dL) 7.64 4.76 3.16 2.58 0.7-1.2
Glucose (mg/dL) 109 167 115 138 70-140
Calcium (mg/dL) 8.4 8.3 8.0 8.7 8.8-10.2
WBC count (10 × 3/µL) 8.4 14.1 15.1 Not obtained 4-10
Hemoglobin (g/dL) 9.5 10.4 9.5 Not obtained 13.5-18
Platelets (10 × 3/µL) 309 121 245 Not obtained 150-400
Absolute eosinophil count (10 × 3/µL) 1.48 0.01 0.21 Not obtained 0-0.5
Despite stopping nitrofurantoin during admission, the patient’s creatinine remained elevated around 7.5 mg/dL, and nephrology was consulted. The patient exhibited features of uremia such as decreased appetite, nausea, and asterixis, warranting renal replacement therapy as per nephrology recommendation. The patient underwent 2 sessions of hemodialysis on day 4 and day 5 of admission and a percutaneous renal biopsy on day 4 to evaluate for etiology of renal failure. Renal biopsy revealed a moderately intense inflammatory infiltrate comprising predominantly of lymphocytes and histiocytes that were admixed with multifocal clusters of eosinophils and few plasma cells (Figure 1). Renal interstitium demonstrated a few scattered noncaseating granulomas with multinucleated giant cells consistent with acute GIN (Figures 2 and 3). There was mild to moderate interstitial fibrosis and tubular atrophy, admixed with interstitial edema, patchy acute tubular necrosis, and congestion of peritubular capillaries. Glomeruli were normal by light microscopy and immunofluorescent, and electron microscopy was negative for immune-complex deposits in the glomeruli. A Ziehl-Neelsen stain for acid-fast bacilli and Gomori methenamine silver stain for fungus was negative. Further testing included angiotensin-converting enzyme level, and the QuantiFERON tuberculosis test returned negative. Computed tomography scan of thorax and abdomen showed incidental small scarring, granulomas, and calcification in the right lung, intrathoracic lymph nodes, and spleen. Although the patient did not have known history of histoplasmosis, as per the infectious disease recommendation, those incidental findings were deemed to be secondary to old resolved histoplasmosis, which the patient might not have been aware of and did not warrant further evaluation and treatment in the absence of pulmonary or constitutional symptoms.
Figure 1. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating dense interstitial inflammation consisting of eosinophils and lymphocytes surrounding the glomeruli and renal tubules.
Figure 2. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating scattered noncaseating granulomas and well-developed granuloma in the renal interstitium. The surrounding interstitial space shows scattered eosinophils.
Figure 3. Hematoxylin and eosin stain at ×400 magnification on light microscopy demonstrating multinucleated giant cells.
The patient was started on prednisone 60 mg on day 4 of admission with resultant significant improvement of her renal function, creatinine 2.8 mg/dL at discharge (Table 1). The patient’s visual hallucinations were attributed to amantadine toxicity from decreased renal excretion, which was gradually tapered and stopped leading to a subsequent visual hallucination resolution. The patient was discharged on a 30-day steroid taper with an outpatient nephrology follow-up. The patient’s most recent renal function test after 2 months showed a serum creatinine of 1.71 mg/dL. She has remained stable from nephrology standpoint.
Discussion
The clinical features associated with AIN are fever, rash, arthralgia, oliguria, and laboratory features include eosinophilia, proteinuria, and leukocyturia.1,3 Although our patient did not have all the systemic features associated with AIN, the presence of peripheral eosinophilia and a history of prolonged nitrofurantoin use were clinical clues that led to suspicion of AIN. The renal pathology further confirmed the diagnosis of AIN with granulomas. Moreover, the patients with granulomatous AIN tend to relatively lack the typical systemic manifestation as compared with the nongranulomatous counterpart.5
Other causes of GIN excluding drugs include sarcoidosis, tuberculosis, fungal infections, and tubulointerstitial interstitial nephritis with uveitis.4 In our case, the special stains for fungus and tuberculosis were negative, which ruled out infectious causes. Even though there was an incidental finding of calcified granulomas in the lungs and spleen, the acute GIN was considered a separate process given the temporal association with nitrofurantoin use and improvement of renal function after discontinuation of nitrofurantoin and steroid administration. Sarcoidosis was considered as one of the differentials in our patient with noncaseating granulomas. However, the renal biopsy, showing the presence of eosinophilic infiltrate with peripheral eosinophilia, absence of pulmonary symptoms, normal serum calcium, and normal angiotensin-converting enzyme, made the diagnosis unlikely.4,6
The drug-induced AIN is believed to be pathologically associated with the immunological process given its association with features of hypersensitivity and the fact that only a few patients exposed to a particular drug develop AIN, with a tendency of recurrence after repeat exposure to the drug.1,4 The pathogenesis for the development of epithelioid granulomas is not well understood in drug-induced interstitial nephritis. Still, it has been attributed to a delayed-type hypersensitivity reaction, and cell-mediated type 1 helper T cells response.4,5 The definitive diagnosis of AIN is made by renal biopsy, which characteristically shows interstitial edema, interstitial infiltrates predominantly composed of macrophages, plasma cells, and eosinophils.1 In our patient, it was unclear if the patient was taking nitrofurantoin for presumed UTI or recurrent UTI as the patient used to follow-up with urologist in Arizona and the records were not readily available and the patient herself was not aware of the situation. It is also unclear why the prescription was written in such a way that would allow her to refill the medication for more than 3 months.
The mainstay management of acute drug-induced GIN is the discontinuation of the offending agent.1 No therapeutic trials exist to assess the efficacy of steroids.4,7 In 2 such cases of acute nitrofurantoin–associated GIN reported by Korzets et al5 and Namagondlu et al,6 the renal function recovered with the withdrawal of nitrofurantoin alone without administration of corticosteroids. In their retrospective study, González et al7 noted that the delayed onset of steroid treatment was associated with the risk of incomplete renal recovery, suggesting early administration of steroid treatment might be essential in patients with drug-induced AIN. Similarly, in another retrospective study, Joss et al8 reported that administration of a moderate dosage of steroids was associated with a favorable prognosis in GIN irrespective of the underlying etiology and the degree of interstitial fibrosis. Nevertheless, our patient had significant renal function improvement with the early administration of steroids as soon as the diagnosis of AIN was confirmed.
Conclusion
With this case report, we would like to report a rare association of acute GIN with nitrofurantoin use successfully treated with the withdrawal of this agent and corticosteroid administration. We want to reiterate the importance of drug-induced interstitial nephritis in AKI and the role of early renal biopsy on establishing the diagnosis of AIN.
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.
Ethical Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Informed consent for patient anonymized information to be published in this article was not obtained from the patient because our institution does not require informed consent for individual case reports.
ORCID iD: Anupama B. K. https://orcid.org/0000-0002-6345-8153 | AMANTADINE HYDROCHLORIDE, NITROFURANTOIN | DrugsGivenReaction | CC BY-NC | 33733898 | 19,323,988 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Glomerulonephritis acute'. | Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis.
We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.
Introduction
Acute interstitial nephritis (AIN) is one of the common causes of acute kidney injury (AKI) and is associated with the presence of inflammatory infiltrates within the renal interstitium.1 AIN has been associated with 15% to 27% of patients with kidney dysfunction.1,2 However, the true incidence of AIN remains largely unrecognized as biopsy might not be sent in cases of clinical suspicion, and milder cases of AIN go undetected.1 There are many causes of AIN, with drug-induced AIN being the most common cause accounting for approximately 70% of all cases.3 Granulomatous interstitial nephritis (GIN) is a rare pathological feature seen in only 0.5% to 0.9% of all kidney biopsies.4 Although nitrofurantoin is a common cause of AIN, GIN is a rare entity. To our knowledge, there are only 2 case reports in the literature describing this condition.5,6 The knowledge of GIN is primarily based on case reports and case series. We present a case of a 71-year-old female with AKI found to have acute GIN on renal biopsy attributed to nitrofurantoin use.
Case Presentation
A 71-year-old female with a past medical history of multiple sclerosis and stress incontinence secondary to cystocele initially presented to her primary care physician with complaints of worsening lower extremity spasms and a new-onset visual hallucination. Routine basal metabolic panel performed for her symptoms incidentally revealed acute renal failure with a serum creatinine of 8.18 mg/dL. She was referred to the nearby hospital where she received 2-L boluses followed by maintenance intravenous fluids without significant improvement of kidney function. The patient was subsequently transferred to our institution for further workup and evaluation by nephrology. The patient’s baseline renal function was reportedly normal 3 months ago. She denied fever, chills, shortness of breath, skin rash, decreased urination, and other urinary symptoms on presentation. She was on long-term amantadine for fatigue related to multiple sclerosis. The patient used to follow-up with an urologist in Arizona for stress incontinence. She was scheduled to undergo an elective urological procedure for stress incontinence and was instructed to take nitrofurantoin 100 mg twice daily for 7 days before the procedure for presumed urinary tract infection (UTI). However, due to the coronavirus disease 2019 pandemic, her elective procedure was canceled, but she continued to take nitrofurantoin 100 mg twice daily for over 3 months for unknown reason. Clinical examination was remarkable for lethargy and altered mental status. Lungs were clear to auscultation bilaterally. The patient was afebrile, and vitals were within normal limits.
Laboratory workup confirmed AKI with a serum creatinine of 7.6 mg/dL and blood urea nitrogen of 60 mg/dL. Urine microscopy was bland without white blood cell, red blood cell, or protein, and urine cultures were negative for infection. Urine protein/creatinine ratio was 0.20 mg/mg. Liver function tests and serum albumin were within normal limits. Complete blood count demonstrated elevated absolute eosinophil count (1.8 × 103/µL). The serial laboratory tests and reference range are detailed in Table 1. Renal ultrasound was unremarkable with no evidence of renal calculi or hydronephrosis. Further workup including vasculitic screening, autoimmune panel, serum immunoglobulins, serum protein immunoelectrophoresis, complement level, hepatitis B and C, and parathyroid hormone level returned normal.
Table 1. Serial Laboratory Values.
Laboratory values (units) Day 1 Day 7 Day 14 Day 16 Reference ranges
Sodium (mmol/L) 140 139 143 144 136-145
Potassium (mmol/L) 4.5 4.0 3.5 3.8 3.4-5.1
Chloride (mmol/L) 108 101 101 106 98-107
Bicarbonate (mmol/L) 18 27 26 26 22-29
Blood urea nitrogen (mg/dL) 60 58 54 39 8-23
Creatinine (mg/dL) 7.64 4.76 3.16 2.58 0.7-1.2
Glucose (mg/dL) 109 167 115 138 70-140
Calcium (mg/dL) 8.4 8.3 8.0 8.7 8.8-10.2
WBC count (10 × 3/µL) 8.4 14.1 15.1 Not obtained 4-10
Hemoglobin (g/dL) 9.5 10.4 9.5 Not obtained 13.5-18
Platelets (10 × 3/µL) 309 121 245 Not obtained 150-400
Absolute eosinophil count (10 × 3/µL) 1.48 0.01 0.21 Not obtained 0-0.5
Despite stopping nitrofurantoin during admission, the patient’s creatinine remained elevated around 7.5 mg/dL, and nephrology was consulted. The patient exhibited features of uremia such as decreased appetite, nausea, and asterixis, warranting renal replacement therapy as per nephrology recommendation. The patient underwent 2 sessions of hemodialysis on day 4 and day 5 of admission and a percutaneous renal biopsy on day 4 to evaluate for etiology of renal failure. Renal biopsy revealed a moderately intense inflammatory infiltrate comprising predominantly of lymphocytes and histiocytes that were admixed with multifocal clusters of eosinophils and few plasma cells (Figure 1). Renal interstitium demonstrated a few scattered noncaseating granulomas with multinucleated giant cells consistent with acute GIN (Figures 2 and 3). There was mild to moderate interstitial fibrosis and tubular atrophy, admixed with interstitial edema, patchy acute tubular necrosis, and congestion of peritubular capillaries. Glomeruli were normal by light microscopy and immunofluorescent, and electron microscopy was negative for immune-complex deposits in the glomeruli. A Ziehl-Neelsen stain for acid-fast bacilli and Gomori methenamine silver stain for fungus was negative. Further testing included angiotensin-converting enzyme level, and the QuantiFERON tuberculosis test returned negative. Computed tomography scan of thorax and abdomen showed incidental small scarring, granulomas, and calcification in the right lung, intrathoracic lymph nodes, and spleen. Although the patient did not have known history of histoplasmosis, as per the infectious disease recommendation, those incidental findings were deemed to be secondary to old resolved histoplasmosis, which the patient might not have been aware of and did not warrant further evaluation and treatment in the absence of pulmonary or constitutional symptoms.
Figure 1. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating dense interstitial inflammation consisting of eosinophils and lymphocytes surrounding the glomeruli and renal tubules.
Figure 2. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating scattered noncaseating granulomas and well-developed granuloma in the renal interstitium. The surrounding interstitial space shows scattered eosinophils.
Figure 3. Hematoxylin and eosin stain at ×400 magnification on light microscopy demonstrating multinucleated giant cells.
The patient was started on prednisone 60 mg on day 4 of admission with resultant significant improvement of her renal function, creatinine 2.8 mg/dL at discharge (Table 1). The patient’s visual hallucinations were attributed to amantadine toxicity from decreased renal excretion, which was gradually tapered and stopped leading to a subsequent visual hallucination resolution. The patient was discharged on a 30-day steroid taper with an outpatient nephrology follow-up. The patient’s most recent renal function test after 2 months showed a serum creatinine of 1.71 mg/dL. She has remained stable from nephrology standpoint.
Discussion
The clinical features associated with AIN are fever, rash, arthralgia, oliguria, and laboratory features include eosinophilia, proteinuria, and leukocyturia.1,3 Although our patient did not have all the systemic features associated with AIN, the presence of peripheral eosinophilia and a history of prolonged nitrofurantoin use were clinical clues that led to suspicion of AIN. The renal pathology further confirmed the diagnosis of AIN with granulomas. Moreover, the patients with granulomatous AIN tend to relatively lack the typical systemic manifestation as compared with the nongranulomatous counterpart.5
Other causes of GIN excluding drugs include sarcoidosis, tuberculosis, fungal infections, and tubulointerstitial interstitial nephritis with uveitis.4 In our case, the special stains for fungus and tuberculosis were negative, which ruled out infectious causes. Even though there was an incidental finding of calcified granulomas in the lungs and spleen, the acute GIN was considered a separate process given the temporal association with nitrofurantoin use and improvement of renal function after discontinuation of nitrofurantoin and steroid administration. Sarcoidosis was considered as one of the differentials in our patient with noncaseating granulomas. However, the renal biopsy, showing the presence of eosinophilic infiltrate with peripheral eosinophilia, absence of pulmonary symptoms, normal serum calcium, and normal angiotensin-converting enzyme, made the diagnosis unlikely.4,6
The drug-induced AIN is believed to be pathologically associated with the immunological process given its association with features of hypersensitivity and the fact that only a few patients exposed to a particular drug develop AIN, with a tendency of recurrence after repeat exposure to the drug.1,4 The pathogenesis for the development of epithelioid granulomas is not well understood in drug-induced interstitial nephritis. Still, it has been attributed to a delayed-type hypersensitivity reaction, and cell-mediated type 1 helper T cells response.4,5 The definitive diagnosis of AIN is made by renal biopsy, which characteristically shows interstitial edema, interstitial infiltrates predominantly composed of macrophages, plasma cells, and eosinophils.1 In our patient, it was unclear if the patient was taking nitrofurantoin for presumed UTI or recurrent UTI as the patient used to follow-up with urologist in Arizona and the records were not readily available and the patient herself was not aware of the situation. It is also unclear why the prescription was written in such a way that would allow her to refill the medication for more than 3 months.
The mainstay management of acute drug-induced GIN is the discontinuation of the offending agent.1 No therapeutic trials exist to assess the efficacy of steroids.4,7 In 2 such cases of acute nitrofurantoin–associated GIN reported by Korzets et al5 and Namagondlu et al,6 the renal function recovered with the withdrawal of nitrofurantoin alone without administration of corticosteroids. In their retrospective study, González et al7 noted that the delayed onset of steroid treatment was associated with the risk of incomplete renal recovery, suggesting early administration of steroid treatment might be essential in patients with drug-induced AIN. Similarly, in another retrospective study, Joss et al8 reported that administration of a moderate dosage of steroids was associated with a favorable prognosis in GIN irrespective of the underlying etiology and the degree of interstitial fibrosis. Nevertheless, our patient had significant renal function improvement with the early administration of steroids as soon as the diagnosis of AIN was confirmed.
Conclusion
With this case report, we would like to report a rare association of acute GIN with nitrofurantoin use successfully treated with the withdrawal of this agent and corticosteroid administration. We want to reiterate the importance of drug-induced interstitial nephritis in AKI and the role of early renal biopsy on establishing the diagnosis of AIN.
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.
Ethical Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Informed consent for patient anonymized information to be published in this article was not obtained from the patient because our institution does not require informed consent for individual case reports.
ORCID iD: Anupama B. K. https://orcid.org/0000-0002-6345-8153 | AMANTADINE HYDROCHLORIDE, NITROFURANTOIN | DrugsGivenReaction | CC BY-NC | 33733898 | 19,376,834 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Granuloma'. | Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis.
We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.
Introduction
Acute interstitial nephritis (AIN) is one of the common causes of acute kidney injury (AKI) and is associated with the presence of inflammatory infiltrates within the renal interstitium.1 AIN has been associated with 15% to 27% of patients with kidney dysfunction.1,2 However, the true incidence of AIN remains largely unrecognized as biopsy might not be sent in cases of clinical suspicion, and milder cases of AIN go undetected.1 There are many causes of AIN, with drug-induced AIN being the most common cause accounting for approximately 70% of all cases.3 Granulomatous interstitial nephritis (GIN) is a rare pathological feature seen in only 0.5% to 0.9% of all kidney biopsies.4 Although nitrofurantoin is a common cause of AIN, GIN is a rare entity. To our knowledge, there are only 2 case reports in the literature describing this condition.5,6 The knowledge of GIN is primarily based on case reports and case series. We present a case of a 71-year-old female with AKI found to have acute GIN on renal biopsy attributed to nitrofurantoin use.
Case Presentation
A 71-year-old female with a past medical history of multiple sclerosis and stress incontinence secondary to cystocele initially presented to her primary care physician with complaints of worsening lower extremity spasms and a new-onset visual hallucination. Routine basal metabolic panel performed for her symptoms incidentally revealed acute renal failure with a serum creatinine of 8.18 mg/dL. She was referred to the nearby hospital where she received 2-L boluses followed by maintenance intravenous fluids without significant improvement of kidney function. The patient was subsequently transferred to our institution for further workup and evaluation by nephrology. The patient’s baseline renal function was reportedly normal 3 months ago. She denied fever, chills, shortness of breath, skin rash, decreased urination, and other urinary symptoms on presentation. She was on long-term amantadine for fatigue related to multiple sclerosis. The patient used to follow-up with an urologist in Arizona for stress incontinence. She was scheduled to undergo an elective urological procedure for stress incontinence and was instructed to take nitrofurantoin 100 mg twice daily for 7 days before the procedure for presumed urinary tract infection (UTI). However, due to the coronavirus disease 2019 pandemic, her elective procedure was canceled, but she continued to take nitrofurantoin 100 mg twice daily for over 3 months for unknown reason. Clinical examination was remarkable for lethargy and altered mental status. Lungs were clear to auscultation bilaterally. The patient was afebrile, and vitals were within normal limits.
Laboratory workup confirmed AKI with a serum creatinine of 7.6 mg/dL and blood urea nitrogen of 60 mg/dL. Urine microscopy was bland without white blood cell, red blood cell, or protein, and urine cultures were negative for infection. Urine protein/creatinine ratio was 0.20 mg/mg. Liver function tests and serum albumin were within normal limits. Complete blood count demonstrated elevated absolute eosinophil count (1.8 × 103/µL). The serial laboratory tests and reference range are detailed in Table 1. Renal ultrasound was unremarkable with no evidence of renal calculi or hydronephrosis. Further workup including vasculitic screening, autoimmune panel, serum immunoglobulins, serum protein immunoelectrophoresis, complement level, hepatitis B and C, and parathyroid hormone level returned normal.
Table 1. Serial Laboratory Values.
Laboratory values (units) Day 1 Day 7 Day 14 Day 16 Reference ranges
Sodium (mmol/L) 140 139 143 144 136-145
Potassium (mmol/L) 4.5 4.0 3.5 3.8 3.4-5.1
Chloride (mmol/L) 108 101 101 106 98-107
Bicarbonate (mmol/L) 18 27 26 26 22-29
Blood urea nitrogen (mg/dL) 60 58 54 39 8-23
Creatinine (mg/dL) 7.64 4.76 3.16 2.58 0.7-1.2
Glucose (mg/dL) 109 167 115 138 70-140
Calcium (mg/dL) 8.4 8.3 8.0 8.7 8.8-10.2
WBC count (10 × 3/µL) 8.4 14.1 15.1 Not obtained 4-10
Hemoglobin (g/dL) 9.5 10.4 9.5 Not obtained 13.5-18
Platelets (10 × 3/µL) 309 121 245 Not obtained 150-400
Absolute eosinophil count (10 × 3/µL) 1.48 0.01 0.21 Not obtained 0-0.5
Despite stopping nitrofurantoin during admission, the patient’s creatinine remained elevated around 7.5 mg/dL, and nephrology was consulted. The patient exhibited features of uremia such as decreased appetite, nausea, and asterixis, warranting renal replacement therapy as per nephrology recommendation. The patient underwent 2 sessions of hemodialysis on day 4 and day 5 of admission and a percutaneous renal biopsy on day 4 to evaluate for etiology of renal failure. Renal biopsy revealed a moderately intense inflammatory infiltrate comprising predominantly of lymphocytes and histiocytes that were admixed with multifocal clusters of eosinophils and few plasma cells (Figure 1). Renal interstitium demonstrated a few scattered noncaseating granulomas with multinucleated giant cells consistent with acute GIN (Figures 2 and 3). There was mild to moderate interstitial fibrosis and tubular atrophy, admixed with interstitial edema, patchy acute tubular necrosis, and congestion of peritubular capillaries. Glomeruli were normal by light microscopy and immunofluorescent, and electron microscopy was negative for immune-complex deposits in the glomeruli. A Ziehl-Neelsen stain for acid-fast bacilli and Gomori methenamine silver stain for fungus was negative. Further testing included angiotensin-converting enzyme level, and the QuantiFERON tuberculosis test returned negative. Computed tomography scan of thorax and abdomen showed incidental small scarring, granulomas, and calcification in the right lung, intrathoracic lymph nodes, and spleen. Although the patient did not have known history of histoplasmosis, as per the infectious disease recommendation, those incidental findings were deemed to be secondary to old resolved histoplasmosis, which the patient might not have been aware of and did not warrant further evaluation and treatment in the absence of pulmonary or constitutional symptoms.
Figure 1. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating dense interstitial inflammation consisting of eosinophils and lymphocytes surrounding the glomeruli and renal tubules.
Figure 2. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating scattered noncaseating granulomas and well-developed granuloma in the renal interstitium. The surrounding interstitial space shows scattered eosinophils.
Figure 3. Hematoxylin and eosin stain at ×400 magnification on light microscopy demonstrating multinucleated giant cells.
The patient was started on prednisone 60 mg on day 4 of admission with resultant significant improvement of her renal function, creatinine 2.8 mg/dL at discharge (Table 1). The patient’s visual hallucinations were attributed to amantadine toxicity from decreased renal excretion, which was gradually tapered and stopped leading to a subsequent visual hallucination resolution. The patient was discharged on a 30-day steroid taper with an outpatient nephrology follow-up. The patient’s most recent renal function test after 2 months showed a serum creatinine of 1.71 mg/dL. She has remained stable from nephrology standpoint.
Discussion
The clinical features associated with AIN are fever, rash, arthralgia, oliguria, and laboratory features include eosinophilia, proteinuria, and leukocyturia.1,3 Although our patient did not have all the systemic features associated with AIN, the presence of peripheral eosinophilia and a history of prolonged nitrofurantoin use were clinical clues that led to suspicion of AIN. The renal pathology further confirmed the diagnosis of AIN with granulomas. Moreover, the patients with granulomatous AIN tend to relatively lack the typical systemic manifestation as compared with the nongranulomatous counterpart.5
Other causes of GIN excluding drugs include sarcoidosis, tuberculosis, fungal infections, and tubulointerstitial interstitial nephritis with uveitis.4 In our case, the special stains for fungus and tuberculosis were negative, which ruled out infectious causes. Even though there was an incidental finding of calcified granulomas in the lungs and spleen, the acute GIN was considered a separate process given the temporal association with nitrofurantoin use and improvement of renal function after discontinuation of nitrofurantoin and steroid administration. Sarcoidosis was considered as one of the differentials in our patient with noncaseating granulomas. However, the renal biopsy, showing the presence of eosinophilic infiltrate with peripheral eosinophilia, absence of pulmonary symptoms, normal serum calcium, and normal angiotensin-converting enzyme, made the diagnosis unlikely.4,6
The drug-induced AIN is believed to be pathologically associated with the immunological process given its association with features of hypersensitivity and the fact that only a few patients exposed to a particular drug develop AIN, with a tendency of recurrence after repeat exposure to the drug.1,4 The pathogenesis for the development of epithelioid granulomas is not well understood in drug-induced interstitial nephritis. Still, it has been attributed to a delayed-type hypersensitivity reaction, and cell-mediated type 1 helper T cells response.4,5 The definitive diagnosis of AIN is made by renal biopsy, which characteristically shows interstitial edema, interstitial infiltrates predominantly composed of macrophages, plasma cells, and eosinophils.1 In our patient, it was unclear if the patient was taking nitrofurantoin for presumed UTI or recurrent UTI as the patient used to follow-up with urologist in Arizona and the records were not readily available and the patient herself was not aware of the situation. It is also unclear why the prescription was written in such a way that would allow her to refill the medication for more than 3 months.
The mainstay management of acute drug-induced GIN is the discontinuation of the offending agent.1 No therapeutic trials exist to assess the efficacy of steroids.4,7 In 2 such cases of acute nitrofurantoin–associated GIN reported by Korzets et al5 and Namagondlu et al,6 the renal function recovered with the withdrawal of nitrofurantoin alone without administration of corticosteroids. In their retrospective study, González et al7 noted that the delayed onset of steroid treatment was associated with the risk of incomplete renal recovery, suggesting early administration of steroid treatment might be essential in patients with drug-induced AIN. Similarly, in another retrospective study, Joss et al8 reported that administration of a moderate dosage of steroids was associated with a favorable prognosis in GIN irrespective of the underlying etiology and the degree of interstitial fibrosis. Nevertheless, our patient had significant renal function improvement with the early administration of steroids as soon as the diagnosis of AIN was confirmed.
Conclusion
With this case report, we would like to report a rare association of acute GIN with nitrofurantoin use successfully treated with the withdrawal of this agent and corticosteroid administration. We want to reiterate the importance of drug-induced interstitial nephritis in AKI and the role of early renal biopsy on establishing the diagnosis of AIN.
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.
Ethical Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Informed consent for patient anonymized information to be published in this article was not obtained from the patient because our institution does not require informed consent for individual case reports.
ORCID iD: Anupama B. K. https://orcid.org/0000-0002-6345-8153 | AMANTADINE HYDROCHLORIDE, NITROFURANTOIN | DrugsGivenReaction | CC BY-NC | 33733898 | 19,323,988 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Medication error'. | Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis.
We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.
Introduction
Acute interstitial nephritis (AIN) is one of the common causes of acute kidney injury (AKI) and is associated with the presence of inflammatory infiltrates within the renal interstitium.1 AIN has been associated with 15% to 27% of patients with kidney dysfunction.1,2 However, the true incidence of AIN remains largely unrecognized as biopsy might not be sent in cases of clinical suspicion, and milder cases of AIN go undetected.1 There are many causes of AIN, with drug-induced AIN being the most common cause accounting for approximately 70% of all cases.3 Granulomatous interstitial nephritis (GIN) is a rare pathological feature seen in only 0.5% to 0.9% of all kidney biopsies.4 Although nitrofurantoin is a common cause of AIN, GIN is a rare entity. To our knowledge, there are only 2 case reports in the literature describing this condition.5,6 The knowledge of GIN is primarily based on case reports and case series. We present a case of a 71-year-old female with AKI found to have acute GIN on renal biopsy attributed to nitrofurantoin use.
Case Presentation
A 71-year-old female with a past medical history of multiple sclerosis and stress incontinence secondary to cystocele initially presented to her primary care physician with complaints of worsening lower extremity spasms and a new-onset visual hallucination. Routine basal metabolic panel performed for her symptoms incidentally revealed acute renal failure with a serum creatinine of 8.18 mg/dL. She was referred to the nearby hospital where she received 2-L boluses followed by maintenance intravenous fluids without significant improvement of kidney function. The patient was subsequently transferred to our institution for further workup and evaluation by nephrology. The patient’s baseline renal function was reportedly normal 3 months ago. She denied fever, chills, shortness of breath, skin rash, decreased urination, and other urinary symptoms on presentation. She was on long-term amantadine for fatigue related to multiple sclerosis. The patient used to follow-up with an urologist in Arizona for stress incontinence. She was scheduled to undergo an elective urological procedure for stress incontinence and was instructed to take nitrofurantoin 100 mg twice daily for 7 days before the procedure for presumed urinary tract infection (UTI). However, due to the coronavirus disease 2019 pandemic, her elective procedure was canceled, but she continued to take nitrofurantoin 100 mg twice daily for over 3 months for unknown reason. Clinical examination was remarkable for lethargy and altered mental status. Lungs were clear to auscultation bilaterally. The patient was afebrile, and vitals were within normal limits.
Laboratory workup confirmed AKI with a serum creatinine of 7.6 mg/dL and blood urea nitrogen of 60 mg/dL. Urine microscopy was bland without white blood cell, red blood cell, or protein, and urine cultures were negative for infection. Urine protein/creatinine ratio was 0.20 mg/mg. Liver function tests and serum albumin were within normal limits. Complete blood count demonstrated elevated absolute eosinophil count (1.8 × 103/µL). The serial laboratory tests and reference range are detailed in Table 1. Renal ultrasound was unremarkable with no evidence of renal calculi or hydronephrosis. Further workup including vasculitic screening, autoimmune panel, serum immunoglobulins, serum protein immunoelectrophoresis, complement level, hepatitis B and C, and parathyroid hormone level returned normal.
Table 1. Serial Laboratory Values.
Laboratory values (units) Day 1 Day 7 Day 14 Day 16 Reference ranges
Sodium (mmol/L) 140 139 143 144 136-145
Potassium (mmol/L) 4.5 4.0 3.5 3.8 3.4-5.1
Chloride (mmol/L) 108 101 101 106 98-107
Bicarbonate (mmol/L) 18 27 26 26 22-29
Blood urea nitrogen (mg/dL) 60 58 54 39 8-23
Creatinine (mg/dL) 7.64 4.76 3.16 2.58 0.7-1.2
Glucose (mg/dL) 109 167 115 138 70-140
Calcium (mg/dL) 8.4 8.3 8.0 8.7 8.8-10.2
WBC count (10 × 3/µL) 8.4 14.1 15.1 Not obtained 4-10
Hemoglobin (g/dL) 9.5 10.4 9.5 Not obtained 13.5-18
Platelets (10 × 3/µL) 309 121 245 Not obtained 150-400
Absolute eosinophil count (10 × 3/µL) 1.48 0.01 0.21 Not obtained 0-0.5
Despite stopping nitrofurantoin during admission, the patient’s creatinine remained elevated around 7.5 mg/dL, and nephrology was consulted. The patient exhibited features of uremia such as decreased appetite, nausea, and asterixis, warranting renal replacement therapy as per nephrology recommendation. The patient underwent 2 sessions of hemodialysis on day 4 and day 5 of admission and a percutaneous renal biopsy on day 4 to evaluate for etiology of renal failure. Renal biopsy revealed a moderately intense inflammatory infiltrate comprising predominantly of lymphocytes and histiocytes that were admixed with multifocal clusters of eosinophils and few plasma cells (Figure 1). Renal interstitium demonstrated a few scattered noncaseating granulomas with multinucleated giant cells consistent with acute GIN (Figures 2 and 3). There was mild to moderate interstitial fibrosis and tubular atrophy, admixed with interstitial edema, patchy acute tubular necrosis, and congestion of peritubular capillaries. Glomeruli were normal by light microscopy and immunofluorescent, and electron microscopy was negative for immune-complex deposits in the glomeruli. A Ziehl-Neelsen stain for acid-fast bacilli and Gomori methenamine silver stain for fungus was negative. Further testing included angiotensin-converting enzyme level, and the QuantiFERON tuberculosis test returned negative. Computed tomography scan of thorax and abdomen showed incidental small scarring, granulomas, and calcification in the right lung, intrathoracic lymph nodes, and spleen. Although the patient did not have known history of histoplasmosis, as per the infectious disease recommendation, those incidental findings were deemed to be secondary to old resolved histoplasmosis, which the patient might not have been aware of and did not warrant further evaluation and treatment in the absence of pulmonary or constitutional symptoms.
Figure 1. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating dense interstitial inflammation consisting of eosinophils and lymphocytes surrounding the glomeruli and renal tubules.
Figure 2. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating scattered noncaseating granulomas and well-developed granuloma in the renal interstitium. The surrounding interstitial space shows scattered eosinophils.
Figure 3. Hematoxylin and eosin stain at ×400 magnification on light microscopy demonstrating multinucleated giant cells.
The patient was started on prednisone 60 mg on day 4 of admission with resultant significant improvement of her renal function, creatinine 2.8 mg/dL at discharge (Table 1). The patient’s visual hallucinations were attributed to amantadine toxicity from decreased renal excretion, which was gradually tapered and stopped leading to a subsequent visual hallucination resolution. The patient was discharged on a 30-day steroid taper with an outpatient nephrology follow-up. The patient’s most recent renal function test after 2 months showed a serum creatinine of 1.71 mg/dL. She has remained stable from nephrology standpoint.
Discussion
The clinical features associated with AIN are fever, rash, arthralgia, oliguria, and laboratory features include eosinophilia, proteinuria, and leukocyturia.1,3 Although our patient did not have all the systemic features associated with AIN, the presence of peripheral eosinophilia and a history of prolonged nitrofurantoin use were clinical clues that led to suspicion of AIN. The renal pathology further confirmed the diagnosis of AIN with granulomas. Moreover, the patients with granulomatous AIN tend to relatively lack the typical systemic manifestation as compared with the nongranulomatous counterpart.5
Other causes of GIN excluding drugs include sarcoidosis, tuberculosis, fungal infections, and tubulointerstitial interstitial nephritis with uveitis.4 In our case, the special stains for fungus and tuberculosis were negative, which ruled out infectious causes. Even though there was an incidental finding of calcified granulomas in the lungs and spleen, the acute GIN was considered a separate process given the temporal association with nitrofurantoin use and improvement of renal function after discontinuation of nitrofurantoin and steroid administration. Sarcoidosis was considered as one of the differentials in our patient with noncaseating granulomas. However, the renal biopsy, showing the presence of eosinophilic infiltrate with peripheral eosinophilia, absence of pulmonary symptoms, normal serum calcium, and normal angiotensin-converting enzyme, made the diagnosis unlikely.4,6
The drug-induced AIN is believed to be pathologically associated with the immunological process given its association with features of hypersensitivity and the fact that only a few patients exposed to a particular drug develop AIN, with a tendency of recurrence after repeat exposure to the drug.1,4 The pathogenesis for the development of epithelioid granulomas is not well understood in drug-induced interstitial nephritis. Still, it has been attributed to a delayed-type hypersensitivity reaction, and cell-mediated type 1 helper T cells response.4,5 The definitive diagnosis of AIN is made by renal biopsy, which characteristically shows interstitial edema, interstitial infiltrates predominantly composed of macrophages, plasma cells, and eosinophils.1 In our patient, it was unclear if the patient was taking nitrofurantoin for presumed UTI or recurrent UTI as the patient used to follow-up with urologist in Arizona and the records were not readily available and the patient herself was not aware of the situation. It is also unclear why the prescription was written in such a way that would allow her to refill the medication for more than 3 months.
The mainstay management of acute drug-induced GIN is the discontinuation of the offending agent.1 No therapeutic trials exist to assess the efficacy of steroids.4,7 In 2 such cases of acute nitrofurantoin–associated GIN reported by Korzets et al5 and Namagondlu et al,6 the renal function recovered with the withdrawal of nitrofurantoin alone without administration of corticosteroids. In their retrospective study, González et al7 noted that the delayed onset of steroid treatment was associated with the risk of incomplete renal recovery, suggesting early administration of steroid treatment might be essential in patients with drug-induced AIN. Similarly, in another retrospective study, Joss et al8 reported that administration of a moderate dosage of steroids was associated with a favorable prognosis in GIN irrespective of the underlying etiology and the degree of interstitial fibrosis. Nevertheless, our patient had significant renal function improvement with the early administration of steroids as soon as the diagnosis of AIN was confirmed.
Conclusion
With this case report, we would like to report a rare association of acute GIN with nitrofurantoin use successfully treated with the withdrawal of this agent and corticosteroid administration. We want to reiterate the importance of drug-induced interstitial nephritis in AKI and the role of early renal biopsy on establishing the diagnosis of AIN.
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.
Ethical Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Informed consent for patient anonymized information to be published in this article was not obtained from the patient because our institution does not require informed consent for individual case reports.
ORCID iD: Anupama B. K. https://orcid.org/0000-0002-6345-8153 | AMANTADINE HYDROCHLORIDE, NITROFURANTOIN | DrugsGivenReaction | CC BY-NC | 33733898 | 19,376,834 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product administration error'. | Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis.
We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.
Introduction
Acute interstitial nephritis (AIN) is one of the common causes of acute kidney injury (AKI) and is associated with the presence of inflammatory infiltrates within the renal interstitium.1 AIN has been associated with 15% to 27% of patients with kidney dysfunction.1,2 However, the true incidence of AIN remains largely unrecognized as biopsy might not be sent in cases of clinical suspicion, and milder cases of AIN go undetected.1 There are many causes of AIN, with drug-induced AIN being the most common cause accounting for approximately 70% of all cases.3 Granulomatous interstitial nephritis (GIN) is a rare pathological feature seen in only 0.5% to 0.9% of all kidney biopsies.4 Although nitrofurantoin is a common cause of AIN, GIN is a rare entity. To our knowledge, there are only 2 case reports in the literature describing this condition.5,6 The knowledge of GIN is primarily based on case reports and case series. We present a case of a 71-year-old female with AKI found to have acute GIN on renal biopsy attributed to nitrofurantoin use.
Case Presentation
A 71-year-old female with a past medical history of multiple sclerosis and stress incontinence secondary to cystocele initially presented to her primary care physician with complaints of worsening lower extremity spasms and a new-onset visual hallucination. Routine basal metabolic panel performed for her symptoms incidentally revealed acute renal failure with a serum creatinine of 8.18 mg/dL. She was referred to the nearby hospital where she received 2-L boluses followed by maintenance intravenous fluids without significant improvement of kidney function. The patient was subsequently transferred to our institution for further workup and evaluation by nephrology. The patient’s baseline renal function was reportedly normal 3 months ago. She denied fever, chills, shortness of breath, skin rash, decreased urination, and other urinary symptoms on presentation. She was on long-term amantadine for fatigue related to multiple sclerosis. The patient used to follow-up with an urologist in Arizona for stress incontinence. She was scheduled to undergo an elective urological procedure for stress incontinence and was instructed to take nitrofurantoin 100 mg twice daily for 7 days before the procedure for presumed urinary tract infection (UTI). However, due to the coronavirus disease 2019 pandemic, her elective procedure was canceled, but she continued to take nitrofurantoin 100 mg twice daily for over 3 months for unknown reason. Clinical examination was remarkable for lethargy and altered mental status. Lungs were clear to auscultation bilaterally. The patient was afebrile, and vitals were within normal limits.
Laboratory workup confirmed AKI with a serum creatinine of 7.6 mg/dL and blood urea nitrogen of 60 mg/dL. Urine microscopy was bland without white blood cell, red blood cell, or protein, and urine cultures were negative for infection. Urine protein/creatinine ratio was 0.20 mg/mg. Liver function tests and serum albumin were within normal limits. Complete blood count demonstrated elevated absolute eosinophil count (1.8 × 103/µL). The serial laboratory tests and reference range are detailed in Table 1. Renal ultrasound was unremarkable with no evidence of renal calculi or hydronephrosis. Further workup including vasculitic screening, autoimmune panel, serum immunoglobulins, serum protein immunoelectrophoresis, complement level, hepatitis B and C, and parathyroid hormone level returned normal.
Table 1. Serial Laboratory Values.
Laboratory values (units) Day 1 Day 7 Day 14 Day 16 Reference ranges
Sodium (mmol/L) 140 139 143 144 136-145
Potassium (mmol/L) 4.5 4.0 3.5 3.8 3.4-5.1
Chloride (mmol/L) 108 101 101 106 98-107
Bicarbonate (mmol/L) 18 27 26 26 22-29
Blood urea nitrogen (mg/dL) 60 58 54 39 8-23
Creatinine (mg/dL) 7.64 4.76 3.16 2.58 0.7-1.2
Glucose (mg/dL) 109 167 115 138 70-140
Calcium (mg/dL) 8.4 8.3 8.0 8.7 8.8-10.2
WBC count (10 × 3/µL) 8.4 14.1 15.1 Not obtained 4-10
Hemoglobin (g/dL) 9.5 10.4 9.5 Not obtained 13.5-18
Platelets (10 × 3/µL) 309 121 245 Not obtained 150-400
Absolute eosinophil count (10 × 3/µL) 1.48 0.01 0.21 Not obtained 0-0.5
Despite stopping nitrofurantoin during admission, the patient’s creatinine remained elevated around 7.5 mg/dL, and nephrology was consulted. The patient exhibited features of uremia such as decreased appetite, nausea, and asterixis, warranting renal replacement therapy as per nephrology recommendation. The patient underwent 2 sessions of hemodialysis on day 4 and day 5 of admission and a percutaneous renal biopsy on day 4 to evaluate for etiology of renal failure. Renal biopsy revealed a moderately intense inflammatory infiltrate comprising predominantly of lymphocytes and histiocytes that were admixed with multifocal clusters of eosinophils and few plasma cells (Figure 1). Renal interstitium demonstrated a few scattered noncaseating granulomas with multinucleated giant cells consistent with acute GIN (Figures 2 and 3). There was mild to moderate interstitial fibrosis and tubular atrophy, admixed with interstitial edema, patchy acute tubular necrosis, and congestion of peritubular capillaries. Glomeruli were normal by light microscopy and immunofluorescent, and electron microscopy was negative for immune-complex deposits in the glomeruli. A Ziehl-Neelsen stain for acid-fast bacilli and Gomori methenamine silver stain for fungus was negative. Further testing included angiotensin-converting enzyme level, and the QuantiFERON tuberculosis test returned negative. Computed tomography scan of thorax and abdomen showed incidental small scarring, granulomas, and calcification in the right lung, intrathoracic lymph nodes, and spleen. Although the patient did not have known history of histoplasmosis, as per the infectious disease recommendation, those incidental findings were deemed to be secondary to old resolved histoplasmosis, which the patient might not have been aware of and did not warrant further evaluation and treatment in the absence of pulmonary or constitutional symptoms.
Figure 1. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating dense interstitial inflammation consisting of eosinophils and lymphocytes surrounding the glomeruli and renal tubules.
Figure 2. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating scattered noncaseating granulomas and well-developed granuloma in the renal interstitium. The surrounding interstitial space shows scattered eosinophils.
Figure 3. Hematoxylin and eosin stain at ×400 magnification on light microscopy demonstrating multinucleated giant cells.
The patient was started on prednisone 60 mg on day 4 of admission with resultant significant improvement of her renal function, creatinine 2.8 mg/dL at discharge (Table 1). The patient’s visual hallucinations were attributed to amantadine toxicity from decreased renal excretion, which was gradually tapered and stopped leading to a subsequent visual hallucination resolution. The patient was discharged on a 30-day steroid taper with an outpatient nephrology follow-up. The patient’s most recent renal function test after 2 months showed a serum creatinine of 1.71 mg/dL. She has remained stable from nephrology standpoint.
Discussion
The clinical features associated with AIN are fever, rash, arthralgia, oliguria, and laboratory features include eosinophilia, proteinuria, and leukocyturia.1,3 Although our patient did not have all the systemic features associated with AIN, the presence of peripheral eosinophilia and a history of prolonged nitrofurantoin use were clinical clues that led to suspicion of AIN. The renal pathology further confirmed the diagnosis of AIN with granulomas. Moreover, the patients with granulomatous AIN tend to relatively lack the typical systemic manifestation as compared with the nongranulomatous counterpart.5
Other causes of GIN excluding drugs include sarcoidosis, tuberculosis, fungal infections, and tubulointerstitial interstitial nephritis with uveitis.4 In our case, the special stains for fungus and tuberculosis were negative, which ruled out infectious causes. Even though there was an incidental finding of calcified granulomas in the lungs and spleen, the acute GIN was considered a separate process given the temporal association with nitrofurantoin use and improvement of renal function after discontinuation of nitrofurantoin and steroid administration. Sarcoidosis was considered as one of the differentials in our patient with noncaseating granulomas. However, the renal biopsy, showing the presence of eosinophilic infiltrate with peripheral eosinophilia, absence of pulmonary symptoms, normal serum calcium, and normal angiotensin-converting enzyme, made the diagnosis unlikely.4,6
The drug-induced AIN is believed to be pathologically associated with the immunological process given its association with features of hypersensitivity and the fact that only a few patients exposed to a particular drug develop AIN, with a tendency of recurrence after repeat exposure to the drug.1,4 The pathogenesis for the development of epithelioid granulomas is not well understood in drug-induced interstitial nephritis. Still, it has been attributed to a delayed-type hypersensitivity reaction, and cell-mediated type 1 helper T cells response.4,5 The definitive diagnosis of AIN is made by renal biopsy, which characteristically shows interstitial edema, interstitial infiltrates predominantly composed of macrophages, plasma cells, and eosinophils.1 In our patient, it was unclear if the patient was taking nitrofurantoin for presumed UTI or recurrent UTI as the patient used to follow-up with urologist in Arizona and the records were not readily available and the patient herself was not aware of the situation. It is also unclear why the prescription was written in such a way that would allow her to refill the medication for more than 3 months.
The mainstay management of acute drug-induced GIN is the discontinuation of the offending agent.1 No therapeutic trials exist to assess the efficacy of steroids.4,7 In 2 such cases of acute nitrofurantoin–associated GIN reported by Korzets et al5 and Namagondlu et al,6 the renal function recovered with the withdrawal of nitrofurantoin alone without administration of corticosteroids. In their retrospective study, González et al7 noted that the delayed onset of steroid treatment was associated with the risk of incomplete renal recovery, suggesting early administration of steroid treatment might be essential in patients with drug-induced AIN. Similarly, in another retrospective study, Joss et al8 reported that administration of a moderate dosage of steroids was associated with a favorable prognosis in GIN irrespective of the underlying etiology and the degree of interstitial fibrosis. Nevertheless, our patient had significant renal function improvement with the early administration of steroids as soon as the diagnosis of AIN was confirmed.
Conclusion
With this case report, we would like to report a rare association of acute GIN with nitrofurantoin use successfully treated with the withdrawal of this agent and corticosteroid administration. We want to reiterate the importance of drug-induced interstitial nephritis in AKI and the role of early renal biopsy on establishing the diagnosis of AIN.
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.
Ethical Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Informed consent for patient anonymized information to be published in this article was not obtained from the patient because our institution does not require informed consent for individual case reports.
ORCID iD: Anupama B. K. https://orcid.org/0000-0002-6345-8153 | AMANTADINE HYDROCHLORIDE, NITROFURANTOIN | DrugsGivenReaction | CC BY-NC | 33733898 | 19,323,988 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product prescribing error'. | Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis.
We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.
Introduction
Acute interstitial nephritis (AIN) is one of the common causes of acute kidney injury (AKI) and is associated with the presence of inflammatory infiltrates within the renal interstitium.1 AIN has been associated with 15% to 27% of patients with kidney dysfunction.1,2 However, the true incidence of AIN remains largely unrecognized as biopsy might not be sent in cases of clinical suspicion, and milder cases of AIN go undetected.1 There are many causes of AIN, with drug-induced AIN being the most common cause accounting for approximately 70% of all cases.3 Granulomatous interstitial nephritis (GIN) is a rare pathological feature seen in only 0.5% to 0.9% of all kidney biopsies.4 Although nitrofurantoin is a common cause of AIN, GIN is a rare entity. To our knowledge, there are only 2 case reports in the literature describing this condition.5,6 The knowledge of GIN is primarily based on case reports and case series. We present a case of a 71-year-old female with AKI found to have acute GIN on renal biopsy attributed to nitrofurantoin use.
Case Presentation
A 71-year-old female with a past medical history of multiple sclerosis and stress incontinence secondary to cystocele initially presented to her primary care physician with complaints of worsening lower extremity spasms and a new-onset visual hallucination. Routine basal metabolic panel performed for her symptoms incidentally revealed acute renal failure with a serum creatinine of 8.18 mg/dL. She was referred to the nearby hospital where she received 2-L boluses followed by maintenance intravenous fluids without significant improvement of kidney function. The patient was subsequently transferred to our institution for further workup and evaluation by nephrology. The patient’s baseline renal function was reportedly normal 3 months ago. She denied fever, chills, shortness of breath, skin rash, decreased urination, and other urinary symptoms on presentation. She was on long-term amantadine for fatigue related to multiple sclerosis. The patient used to follow-up with an urologist in Arizona for stress incontinence. She was scheduled to undergo an elective urological procedure for stress incontinence and was instructed to take nitrofurantoin 100 mg twice daily for 7 days before the procedure for presumed urinary tract infection (UTI). However, due to the coronavirus disease 2019 pandemic, her elective procedure was canceled, but she continued to take nitrofurantoin 100 mg twice daily for over 3 months for unknown reason. Clinical examination was remarkable for lethargy and altered mental status. Lungs were clear to auscultation bilaterally. The patient was afebrile, and vitals were within normal limits.
Laboratory workup confirmed AKI with a serum creatinine of 7.6 mg/dL and blood urea nitrogen of 60 mg/dL. Urine microscopy was bland without white blood cell, red blood cell, or protein, and urine cultures were negative for infection. Urine protein/creatinine ratio was 0.20 mg/mg. Liver function tests and serum albumin were within normal limits. Complete blood count demonstrated elevated absolute eosinophil count (1.8 × 103/µL). The serial laboratory tests and reference range are detailed in Table 1. Renal ultrasound was unremarkable with no evidence of renal calculi or hydronephrosis. Further workup including vasculitic screening, autoimmune panel, serum immunoglobulins, serum protein immunoelectrophoresis, complement level, hepatitis B and C, and parathyroid hormone level returned normal.
Table 1. Serial Laboratory Values.
Laboratory values (units) Day 1 Day 7 Day 14 Day 16 Reference ranges
Sodium (mmol/L) 140 139 143 144 136-145
Potassium (mmol/L) 4.5 4.0 3.5 3.8 3.4-5.1
Chloride (mmol/L) 108 101 101 106 98-107
Bicarbonate (mmol/L) 18 27 26 26 22-29
Blood urea nitrogen (mg/dL) 60 58 54 39 8-23
Creatinine (mg/dL) 7.64 4.76 3.16 2.58 0.7-1.2
Glucose (mg/dL) 109 167 115 138 70-140
Calcium (mg/dL) 8.4 8.3 8.0 8.7 8.8-10.2
WBC count (10 × 3/µL) 8.4 14.1 15.1 Not obtained 4-10
Hemoglobin (g/dL) 9.5 10.4 9.5 Not obtained 13.5-18
Platelets (10 × 3/µL) 309 121 245 Not obtained 150-400
Absolute eosinophil count (10 × 3/µL) 1.48 0.01 0.21 Not obtained 0-0.5
Despite stopping nitrofurantoin during admission, the patient’s creatinine remained elevated around 7.5 mg/dL, and nephrology was consulted. The patient exhibited features of uremia such as decreased appetite, nausea, and asterixis, warranting renal replacement therapy as per nephrology recommendation. The patient underwent 2 sessions of hemodialysis on day 4 and day 5 of admission and a percutaneous renal biopsy on day 4 to evaluate for etiology of renal failure. Renal biopsy revealed a moderately intense inflammatory infiltrate comprising predominantly of lymphocytes and histiocytes that were admixed with multifocal clusters of eosinophils and few plasma cells (Figure 1). Renal interstitium demonstrated a few scattered noncaseating granulomas with multinucleated giant cells consistent with acute GIN (Figures 2 and 3). There was mild to moderate interstitial fibrosis and tubular atrophy, admixed with interstitial edema, patchy acute tubular necrosis, and congestion of peritubular capillaries. Glomeruli were normal by light microscopy and immunofluorescent, and electron microscopy was negative for immune-complex deposits in the glomeruli. A Ziehl-Neelsen stain for acid-fast bacilli and Gomori methenamine silver stain for fungus was negative. Further testing included angiotensin-converting enzyme level, and the QuantiFERON tuberculosis test returned negative. Computed tomography scan of thorax and abdomen showed incidental small scarring, granulomas, and calcification in the right lung, intrathoracic lymph nodes, and spleen. Although the patient did not have known history of histoplasmosis, as per the infectious disease recommendation, those incidental findings were deemed to be secondary to old resolved histoplasmosis, which the patient might not have been aware of and did not warrant further evaluation and treatment in the absence of pulmonary or constitutional symptoms.
Figure 1. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating dense interstitial inflammation consisting of eosinophils and lymphocytes surrounding the glomeruli and renal tubules.
Figure 2. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating scattered noncaseating granulomas and well-developed granuloma in the renal interstitium. The surrounding interstitial space shows scattered eosinophils.
Figure 3. Hematoxylin and eosin stain at ×400 magnification on light microscopy demonstrating multinucleated giant cells.
The patient was started on prednisone 60 mg on day 4 of admission with resultant significant improvement of her renal function, creatinine 2.8 mg/dL at discharge (Table 1). The patient’s visual hallucinations were attributed to amantadine toxicity from decreased renal excretion, which was gradually tapered and stopped leading to a subsequent visual hallucination resolution. The patient was discharged on a 30-day steroid taper with an outpatient nephrology follow-up. The patient’s most recent renal function test after 2 months showed a serum creatinine of 1.71 mg/dL. She has remained stable from nephrology standpoint.
Discussion
The clinical features associated with AIN are fever, rash, arthralgia, oliguria, and laboratory features include eosinophilia, proteinuria, and leukocyturia.1,3 Although our patient did not have all the systemic features associated with AIN, the presence of peripheral eosinophilia and a history of prolonged nitrofurantoin use were clinical clues that led to suspicion of AIN. The renal pathology further confirmed the diagnosis of AIN with granulomas. Moreover, the patients with granulomatous AIN tend to relatively lack the typical systemic manifestation as compared with the nongranulomatous counterpart.5
Other causes of GIN excluding drugs include sarcoidosis, tuberculosis, fungal infections, and tubulointerstitial interstitial nephritis with uveitis.4 In our case, the special stains for fungus and tuberculosis were negative, which ruled out infectious causes. Even though there was an incidental finding of calcified granulomas in the lungs and spleen, the acute GIN was considered a separate process given the temporal association with nitrofurantoin use and improvement of renal function after discontinuation of nitrofurantoin and steroid administration. Sarcoidosis was considered as one of the differentials in our patient with noncaseating granulomas. However, the renal biopsy, showing the presence of eosinophilic infiltrate with peripheral eosinophilia, absence of pulmonary symptoms, normal serum calcium, and normal angiotensin-converting enzyme, made the diagnosis unlikely.4,6
The drug-induced AIN is believed to be pathologically associated with the immunological process given its association with features of hypersensitivity and the fact that only a few patients exposed to a particular drug develop AIN, with a tendency of recurrence after repeat exposure to the drug.1,4 The pathogenesis for the development of epithelioid granulomas is not well understood in drug-induced interstitial nephritis. Still, it has been attributed to a delayed-type hypersensitivity reaction, and cell-mediated type 1 helper T cells response.4,5 The definitive diagnosis of AIN is made by renal biopsy, which characteristically shows interstitial edema, interstitial infiltrates predominantly composed of macrophages, plasma cells, and eosinophils.1 In our patient, it was unclear if the patient was taking nitrofurantoin for presumed UTI or recurrent UTI as the patient used to follow-up with urologist in Arizona and the records were not readily available and the patient herself was not aware of the situation. It is also unclear why the prescription was written in such a way that would allow her to refill the medication for more than 3 months.
The mainstay management of acute drug-induced GIN is the discontinuation of the offending agent.1 No therapeutic trials exist to assess the efficacy of steroids.4,7 In 2 such cases of acute nitrofurantoin–associated GIN reported by Korzets et al5 and Namagondlu et al,6 the renal function recovered with the withdrawal of nitrofurantoin alone without administration of corticosteroids. In their retrospective study, González et al7 noted that the delayed onset of steroid treatment was associated with the risk of incomplete renal recovery, suggesting early administration of steroid treatment might be essential in patients with drug-induced AIN. Similarly, in another retrospective study, Joss et al8 reported that administration of a moderate dosage of steroids was associated with a favorable prognosis in GIN irrespective of the underlying etiology and the degree of interstitial fibrosis. Nevertheless, our patient had significant renal function improvement with the early administration of steroids as soon as the diagnosis of AIN was confirmed.
Conclusion
With this case report, we would like to report a rare association of acute GIN with nitrofurantoin use successfully treated with the withdrawal of this agent and corticosteroid administration. We want to reiterate the importance of drug-induced interstitial nephritis in AKI and the role of early renal biopsy on establishing the diagnosis of AIN.
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.
Ethical Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Informed consent for patient anonymized information to be published in this article was not obtained from the patient because our institution does not require informed consent for individual case reports.
ORCID iD: Anupama B. K. https://orcid.org/0000-0002-6345-8153 | AMANTADINE HYDROCHLORIDE, NITROFURANTOIN | DrugsGivenReaction | CC BY-NC | 33733898 | 19,323,988 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis.
We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.
Introduction
Acute interstitial nephritis (AIN) is one of the common causes of acute kidney injury (AKI) and is associated with the presence of inflammatory infiltrates within the renal interstitium.1 AIN has been associated with 15% to 27% of patients with kidney dysfunction.1,2 However, the true incidence of AIN remains largely unrecognized as biopsy might not be sent in cases of clinical suspicion, and milder cases of AIN go undetected.1 There are many causes of AIN, with drug-induced AIN being the most common cause accounting for approximately 70% of all cases.3 Granulomatous interstitial nephritis (GIN) is a rare pathological feature seen in only 0.5% to 0.9% of all kidney biopsies.4 Although nitrofurantoin is a common cause of AIN, GIN is a rare entity. To our knowledge, there are only 2 case reports in the literature describing this condition.5,6 The knowledge of GIN is primarily based on case reports and case series. We present a case of a 71-year-old female with AKI found to have acute GIN on renal biopsy attributed to nitrofurantoin use.
Case Presentation
A 71-year-old female with a past medical history of multiple sclerosis and stress incontinence secondary to cystocele initially presented to her primary care physician with complaints of worsening lower extremity spasms and a new-onset visual hallucination. Routine basal metabolic panel performed for her symptoms incidentally revealed acute renal failure with a serum creatinine of 8.18 mg/dL. She was referred to the nearby hospital where she received 2-L boluses followed by maintenance intravenous fluids without significant improvement of kidney function. The patient was subsequently transferred to our institution for further workup and evaluation by nephrology. The patient’s baseline renal function was reportedly normal 3 months ago. She denied fever, chills, shortness of breath, skin rash, decreased urination, and other urinary symptoms on presentation. She was on long-term amantadine for fatigue related to multiple sclerosis. The patient used to follow-up with an urologist in Arizona for stress incontinence. She was scheduled to undergo an elective urological procedure for stress incontinence and was instructed to take nitrofurantoin 100 mg twice daily for 7 days before the procedure for presumed urinary tract infection (UTI). However, due to the coronavirus disease 2019 pandemic, her elective procedure was canceled, but she continued to take nitrofurantoin 100 mg twice daily for over 3 months for unknown reason. Clinical examination was remarkable for lethargy and altered mental status. Lungs were clear to auscultation bilaterally. The patient was afebrile, and vitals were within normal limits.
Laboratory workup confirmed AKI with a serum creatinine of 7.6 mg/dL and blood urea nitrogen of 60 mg/dL. Urine microscopy was bland without white blood cell, red blood cell, or protein, and urine cultures were negative for infection. Urine protein/creatinine ratio was 0.20 mg/mg. Liver function tests and serum albumin were within normal limits. Complete blood count demonstrated elevated absolute eosinophil count (1.8 × 103/µL). The serial laboratory tests and reference range are detailed in Table 1. Renal ultrasound was unremarkable with no evidence of renal calculi or hydronephrosis. Further workup including vasculitic screening, autoimmune panel, serum immunoglobulins, serum protein immunoelectrophoresis, complement level, hepatitis B and C, and parathyroid hormone level returned normal.
Table 1. Serial Laboratory Values.
Laboratory values (units) Day 1 Day 7 Day 14 Day 16 Reference ranges
Sodium (mmol/L) 140 139 143 144 136-145
Potassium (mmol/L) 4.5 4.0 3.5 3.8 3.4-5.1
Chloride (mmol/L) 108 101 101 106 98-107
Bicarbonate (mmol/L) 18 27 26 26 22-29
Blood urea nitrogen (mg/dL) 60 58 54 39 8-23
Creatinine (mg/dL) 7.64 4.76 3.16 2.58 0.7-1.2
Glucose (mg/dL) 109 167 115 138 70-140
Calcium (mg/dL) 8.4 8.3 8.0 8.7 8.8-10.2
WBC count (10 × 3/µL) 8.4 14.1 15.1 Not obtained 4-10
Hemoglobin (g/dL) 9.5 10.4 9.5 Not obtained 13.5-18
Platelets (10 × 3/µL) 309 121 245 Not obtained 150-400
Absolute eosinophil count (10 × 3/µL) 1.48 0.01 0.21 Not obtained 0-0.5
Despite stopping nitrofurantoin during admission, the patient’s creatinine remained elevated around 7.5 mg/dL, and nephrology was consulted. The patient exhibited features of uremia such as decreased appetite, nausea, and asterixis, warranting renal replacement therapy as per nephrology recommendation. The patient underwent 2 sessions of hemodialysis on day 4 and day 5 of admission and a percutaneous renal biopsy on day 4 to evaluate for etiology of renal failure. Renal biopsy revealed a moderately intense inflammatory infiltrate comprising predominantly of lymphocytes and histiocytes that were admixed with multifocal clusters of eosinophils and few plasma cells (Figure 1). Renal interstitium demonstrated a few scattered noncaseating granulomas with multinucleated giant cells consistent with acute GIN (Figures 2 and 3). There was mild to moderate interstitial fibrosis and tubular atrophy, admixed with interstitial edema, patchy acute tubular necrosis, and congestion of peritubular capillaries. Glomeruli were normal by light microscopy and immunofluorescent, and electron microscopy was negative for immune-complex deposits in the glomeruli. A Ziehl-Neelsen stain for acid-fast bacilli and Gomori methenamine silver stain for fungus was negative. Further testing included angiotensin-converting enzyme level, and the QuantiFERON tuberculosis test returned negative. Computed tomography scan of thorax and abdomen showed incidental small scarring, granulomas, and calcification in the right lung, intrathoracic lymph nodes, and spleen. Although the patient did not have known history of histoplasmosis, as per the infectious disease recommendation, those incidental findings were deemed to be secondary to old resolved histoplasmosis, which the patient might not have been aware of and did not warrant further evaluation and treatment in the absence of pulmonary or constitutional symptoms.
Figure 1. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating dense interstitial inflammation consisting of eosinophils and lymphocytes surrounding the glomeruli and renal tubules.
Figure 2. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating scattered noncaseating granulomas and well-developed granuloma in the renal interstitium. The surrounding interstitial space shows scattered eosinophils.
Figure 3. Hematoxylin and eosin stain at ×400 magnification on light microscopy demonstrating multinucleated giant cells.
The patient was started on prednisone 60 mg on day 4 of admission with resultant significant improvement of her renal function, creatinine 2.8 mg/dL at discharge (Table 1). The patient’s visual hallucinations were attributed to amantadine toxicity from decreased renal excretion, which was gradually tapered and stopped leading to a subsequent visual hallucination resolution. The patient was discharged on a 30-day steroid taper with an outpatient nephrology follow-up. The patient’s most recent renal function test after 2 months showed a serum creatinine of 1.71 mg/dL. She has remained stable from nephrology standpoint.
Discussion
The clinical features associated with AIN are fever, rash, arthralgia, oliguria, and laboratory features include eosinophilia, proteinuria, and leukocyturia.1,3 Although our patient did not have all the systemic features associated with AIN, the presence of peripheral eosinophilia and a history of prolonged nitrofurantoin use were clinical clues that led to suspicion of AIN. The renal pathology further confirmed the diagnosis of AIN with granulomas. Moreover, the patients with granulomatous AIN tend to relatively lack the typical systemic manifestation as compared with the nongranulomatous counterpart.5
Other causes of GIN excluding drugs include sarcoidosis, tuberculosis, fungal infections, and tubulointerstitial interstitial nephritis with uveitis.4 In our case, the special stains for fungus and tuberculosis were negative, which ruled out infectious causes. Even though there was an incidental finding of calcified granulomas in the lungs and spleen, the acute GIN was considered a separate process given the temporal association with nitrofurantoin use and improvement of renal function after discontinuation of nitrofurantoin and steroid administration. Sarcoidosis was considered as one of the differentials in our patient with noncaseating granulomas. However, the renal biopsy, showing the presence of eosinophilic infiltrate with peripheral eosinophilia, absence of pulmonary symptoms, normal serum calcium, and normal angiotensin-converting enzyme, made the diagnosis unlikely.4,6
The drug-induced AIN is believed to be pathologically associated with the immunological process given its association with features of hypersensitivity and the fact that only a few patients exposed to a particular drug develop AIN, with a tendency of recurrence after repeat exposure to the drug.1,4 The pathogenesis for the development of epithelioid granulomas is not well understood in drug-induced interstitial nephritis. Still, it has been attributed to a delayed-type hypersensitivity reaction, and cell-mediated type 1 helper T cells response.4,5 The definitive diagnosis of AIN is made by renal biopsy, which characteristically shows interstitial edema, interstitial infiltrates predominantly composed of macrophages, plasma cells, and eosinophils.1 In our patient, it was unclear if the patient was taking nitrofurantoin for presumed UTI or recurrent UTI as the patient used to follow-up with urologist in Arizona and the records were not readily available and the patient herself was not aware of the situation. It is also unclear why the prescription was written in such a way that would allow her to refill the medication for more than 3 months.
The mainstay management of acute drug-induced GIN is the discontinuation of the offending agent.1 No therapeutic trials exist to assess the efficacy of steroids.4,7 In 2 such cases of acute nitrofurantoin–associated GIN reported by Korzets et al5 and Namagondlu et al,6 the renal function recovered with the withdrawal of nitrofurantoin alone without administration of corticosteroids. In their retrospective study, González et al7 noted that the delayed onset of steroid treatment was associated with the risk of incomplete renal recovery, suggesting early administration of steroid treatment might be essential in patients with drug-induced AIN. Similarly, in another retrospective study, Joss et al8 reported that administration of a moderate dosage of steroids was associated with a favorable prognosis in GIN irrespective of the underlying etiology and the degree of interstitial fibrosis. Nevertheless, our patient had significant renal function improvement with the early administration of steroids as soon as the diagnosis of AIN was confirmed.
Conclusion
With this case report, we would like to report a rare association of acute GIN with nitrofurantoin use successfully treated with the withdrawal of this agent and corticosteroid administration. We want to reiterate the importance of drug-induced interstitial nephritis in AKI and the role of early renal biopsy on establishing the diagnosis of AIN.
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.
Ethical Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Informed consent for patient anonymized information to be published in this article was not obtained from the patient because our institution does not require informed consent for individual case reports.
ORCID iD: Anupama B. K. https://orcid.org/0000-0002-6345-8153 | AMANTADINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33733898 | 19,280,096 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'. | Nitrofurantoin-Associated Acute Granulomatous Interstitial Nephritis.
We report the case of a 71-year-old female who was incidentally found to have nonoliguric acute kidney injury on a routine workup for new-onset visual hallucination. Further history revealed inadvertent usage of nitrofurantoin for 3 months for an anticipated urological procedure. Renal biopsy demonstrated acute granulomatous interstitial nephritis. The renal function significantly improved following discontinuation of nitrofurantoin and corticosteroid administration. We highlight a rare association of nitrofurantoin with acute granulomatous interstitial nephritis through this case report.
Introduction
Acute interstitial nephritis (AIN) is one of the common causes of acute kidney injury (AKI) and is associated with the presence of inflammatory infiltrates within the renal interstitium.1 AIN has been associated with 15% to 27% of patients with kidney dysfunction.1,2 However, the true incidence of AIN remains largely unrecognized as biopsy might not be sent in cases of clinical suspicion, and milder cases of AIN go undetected.1 There are many causes of AIN, with drug-induced AIN being the most common cause accounting for approximately 70% of all cases.3 Granulomatous interstitial nephritis (GIN) is a rare pathological feature seen in only 0.5% to 0.9% of all kidney biopsies.4 Although nitrofurantoin is a common cause of AIN, GIN is a rare entity. To our knowledge, there are only 2 case reports in the literature describing this condition.5,6 The knowledge of GIN is primarily based on case reports and case series. We present a case of a 71-year-old female with AKI found to have acute GIN on renal biopsy attributed to nitrofurantoin use.
Case Presentation
A 71-year-old female with a past medical history of multiple sclerosis and stress incontinence secondary to cystocele initially presented to her primary care physician with complaints of worsening lower extremity spasms and a new-onset visual hallucination. Routine basal metabolic panel performed for her symptoms incidentally revealed acute renal failure with a serum creatinine of 8.18 mg/dL. She was referred to the nearby hospital where she received 2-L boluses followed by maintenance intravenous fluids without significant improvement of kidney function. The patient was subsequently transferred to our institution for further workup and evaluation by nephrology. The patient’s baseline renal function was reportedly normal 3 months ago. She denied fever, chills, shortness of breath, skin rash, decreased urination, and other urinary symptoms on presentation. She was on long-term amantadine for fatigue related to multiple sclerosis. The patient used to follow-up with an urologist in Arizona for stress incontinence. She was scheduled to undergo an elective urological procedure for stress incontinence and was instructed to take nitrofurantoin 100 mg twice daily for 7 days before the procedure for presumed urinary tract infection (UTI). However, due to the coronavirus disease 2019 pandemic, her elective procedure was canceled, but she continued to take nitrofurantoin 100 mg twice daily for over 3 months for unknown reason. Clinical examination was remarkable for lethargy and altered mental status. Lungs were clear to auscultation bilaterally. The patient was afebrile, and vitals were within normal limits.
Laboratory workup confirmed AKI with a serum creatinine of 7.6 mg/dL and blood urea nitrogen of 60 mg/dL. Urine microscopy was bland without white blood cell, red blood cell, or protein, and urine cultures were negative for infection. Urine protein/creatinine ratio was 0.20 mg/mg. Liver function tests and serum albumin were within normal limits. Complete blood count demonstrated elevated absolute eosinophil count (1.8 × 103/µL). The serial laboratory tests and reference range are detailed in Table 1. Renal ultrasound was unremarkable with no evidence of renal calculi or hydronephrosis. Further workup including vasculitic screening, autoimmune panel, serum immunoglobulins, serum protein immunoelectrophoresis, complement level, hepatitis B and C, and parathyroid hormone level returned normal.
Table 1. Serial Laboratory Values.
Laboratory values (units) Day 1 Day 7 Day 14 Day 16 Reference ranges
Sodium (mmol/L) 140 139 143 144 136-145
Potassium (mmol/L) 4.5 4.0 3.5 3.8 3.4-5.1
Chloride (mmol/L) 108 101 101 106 98-107
Bicarbonate (mmol/L) 18 27 26 26 22-29
Blood urea nitrogen (mg/dL) 60 58 54 39 8-23
Creatinine (mg/dL) 7.64 4.76 3.16 2.58 0.7-1.2
Glucose (mg/dL) 109 167 115 138 70-140
Calcium (mg/dL) 8.4 8.3 8.0 8.7 8.8-10.2
WBC count (10 × 3/µL) 8.4 14.1 15.1 Not obtained 4-10
Hemoglobin (g/dL) 9.5 10.4 9.5 Not obtained 13.5-18
Platelets (10 × 3/µL) 309 121 245 Not obtained 150-400
Absolute eosinophil count (10 × 3/µL) 1.48 0.01 0.21 Not obtained 0-0.5
Despite stopping nitrofurantoin during admission, the patient’s creatinine remained elevated around 7.5 mg/dL, and nephrology was consulted. The patient exhibited features of uremia such as decreased appetite, nausea, and asterixis, warranting renal replacement therapy as per nephrology recommendation. The patient underwent 2 sessions of hemodialysis on day 4 and day 5 of admission and a percutaneous renal biopsy on day 4 to evaluate for etiology of renal failure. Renal biopsy revealed a moderately intense inflammatory infiltrate comprising predominantly of lymphocytes and histiocytes that were admixed with multifocal clusters of eosinophils and few plasma cells (Figure 1). Renal interstitium demonstrated a few scattered noncaseating granulomas with multinucleated giant cells consistent with acute GIN (Figures 2 and 3). There was mild to moderate interstitial fibrosis and tubular atrophy, admixed with interstitial edema, patchy acute tubular necrosis, and congestion of peritubular capillaries. Glomeruli were normal by light microscopy and immunofluorescent, and electron microscopy was negative for immune-complex deposits in the glomeruli. A Ziehl-Neelsen stain for acid-fast bacilli and Gomori methenamine silver stain for fungus was negative. Further testing included angiotensin-converting enzyme level, and the QuantiFERON tuberculosis test returned negative. Computed tomography scan of thorax and abdomen showed incidental small scarring, granulomas, and calcification in the right lung, intrathoracic lymph nodes, and spleen. Although the patient did not have known history of histoplasmosis, as per the infectious disease recommendation, those incidental findings were deemed to be secondary to old resolved histoplasmosis, which the patient might not have been aware of and did not warrant further evaluation and treatment in the absence of pulmonary or constitutional symptoms.
Figure 1. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating dense interstitial inflammation consisting of eosinophils and lymphocytes surrounding the glomeruli and renal tubules.
Figure 2. Hematoxylin and eosin stain at ×200 magnification on light microscopy demonstrating scattered noncaseating granulomas and well-developed granuloma in the renal interstitium. The surrounding interstitial space shows scattered eosinophils.
Figure 3. Hematoxylin and eosin stain at ×400 magnification on light microscopy demonstrating multinucleated giant cells.
The patient was started on prednisone 60 mg on day 4 of admission with resultant significant improvement of her renal function, creatinine 2.8 mg/dL at discharge (Table 1). The patient’s visual hallucinations were attributed to amantadine toxicity from decreased renal excretion, which was gradually tapered and stopped leading to a subsequent visual hallucination resolution. The patient was discharged on a 30-day steroid taper with an outpatient nephrology follow-up. The patient’s most recent renal function test after 2 months showed a serum creatinine of 1.71 mg/dL. She has remained stable from nephrology standpoint.
Discussion
The clinical features associated with AIN are fever, rash, arthralgia, oliguria, and laboratory features include eosinophilia, proteinuria, and leukocyturia.1,3 Although our patient did not have all the systemic features associated with AIN, the presence of peripheral eosinophilia and a history of prolonged nitrofurantoin use were clinical clues that led to suspicion of AIN. The renal pathology further confirmed the diagnosis of AIN with granulomas. Moreover, the patients with granulomatous AIN tend to relatively lack the typical systemic manifestation as compared with the nongranulomatous counterpart.5
Other causes of GIN excluding drugs include sarcoidosis, tuberculosis, fungal infections, and tubulointerstitial interstitial nephritis with uveitis.4 In our case, the special stains for fungus and tuberculosis were negative, which ruled out infectious causes. Even though there was an incidental finding of calcified granulomas in the lungs and spleen, the acute GIN was considered a separate process given the temporal association with nitrofurantoin use and improvement of renal function after discontinuation of nitrofurantoin and steroid administration. Sarcoidosis was considered as one of the differentials in our patient with noncaseating granulomas. However, the renal biopsy, showing the presence of eosinophilic infiltrate with peripheral eosinophilia, absence of pulmonary symptoms, normal serum calcium, and normal angiotensin-converting enzyme, made the diagnosis unlikely.4,6
The drug-induced AIN is believed to be pathologically associated with the immunological process given its association with features of hypersensitivity and the fact that only a few patients exposed to a particular drug develop AIN, with a tendency of recurrence after repeat exposure to the drug.1,4 The pathogenesis for the development of epithelioid granulomas is not well understood in drug-induced interstitial nephritis. Still, it has been attributed to a delayed-type hypersensitivity reaction, and cell-mediated type 1 helper T cells response.4,5 The definitive diagnosis of AIN is made by renal biopsy, which characteristically shows interstitial edema, interstitial infiltrates predominantly composed of macrophages, plasma cells, and eosinophils.1 In our patient, it was unclear if the patient was taking nitrofurantoin for presumed UTI or recurrent UTI as the patient used to follow-up with urologist in Arizona and the records were not readily available and the patient herself was not aware of the situation. It is also unclear why the prescription was written in such a way that would allow her to refill the medication for more than 3 months.
The mainstay management of acute drug-induced GIN is the discontinuation of the offending agent.1 No therapeutic trials exist to assess the efficacy of steroids.4,7 In 2 such cases of acute nitrofurantoin–associated GIN reported by Korzets et al5 and Namagondlu et al,6 the renal function recovered with the withdrawal of nitrofurantoin alone without administration of corticosteroids. In their retrospective study, González et al7 noted that the delayed onset of steroid treatment was associated with the risk of incomplete renal recovery, suggesting early administration of steroid treatment might be essential in patients with drug-induced AIN. Similarly, in another retrospective study, Joss et al8 reported that administration of a moderate dosage of steroids was associated with a favorable prognosis in GIN irrespective of the underlying etiology and the degree of interstitial fibrosis. Nevertheless, our patient had significant renal function improvement with the early administration of steroids as soon as the diagnosis of AIN was confirmed.
Conclusion
With this case report, we would like to report a rare association of acute GIN with nitrofurantoin use successfully treated with the withdrawal of this agent and corticosteroid administration. We want to reiterate the importance of drug-induced interstitial nephritis in AKI and the role of early renal biopsy on establishing the diagnosis of AIN.
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.
Ethical Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Informed consent for patient anonymized information to be published in this article was not obtained from the patient because our institution does not require informed consent for individual case reports.
ORCID iD: Anupama B. K. https://orcid.org/0000-0002-6345-8153 | AMANTADINE HYDROCHLORIDE, NITROFURANTOIN | DrugsGivenReaction | CC BY-NC | 33733898 | 19,097,961 | 2021 |
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