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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Transplant rejection'. | Acute heart transplantation from mechanical circulatory support in a human immunodeficiency virus-positive patient with fulminant myocarditis.
Since the establishment of highly active antiretroviral therapy, survival rates have improved among patients with human immunodeficiency virus infection giving them the possibility to become transplant candidates. Recent publications revealed that human immunodeficiency virus-positive heart transplant recipients' survival is similar to non-infected patients. We present the case of a 40-year-old human immunodeficiency virus infected patient, who was hospitalized due to severely decreased left ventricular function with a possible aetiology of acute myocarditis, that has later been confirmed by histological investigation of myocardial biopsy. Due to rapid progression to refractory cardiogenic shock, extracorporeal membrane oxygenation implantation had been initiated, which was upgraded to biventricular assist device later. On the 35th day of upgraded support, the patient underwent heart transplantation uneventfully. Our clinical experience confirms that implementation of temporary mechanical circulatory support and subsequent cardiac transplantation might be successful in human immunodeficiency virus-positive patients even in case of new onset, irreversible acute heart failure.
Introduction
Since the establishment of highly active antiretroviral therapy (HAART), survival rates have improved among patients with human immunodeficiency virus (HIV) infection with a parallel decrease in the incidence of acquired immunodeficiency syndrome, turning HIV infection into a chronic disease. 1 , 2 Nowadays, HIV‐positive patients' life expectancy mostly depends on chronic organ dysfunctions, including chronic hepatic, renal and pulmonary disorders, or cardiomyopathy. 3 The risk of cardiovascular disease and the prevalence of chronic heart failure are significantly higher in HIV‐positive patients as compared with non‐HIV‐infected patients. 3 , 4 , 5 HIV infection had been a contraindication for solid organ transplantation until recently, due to concern about the interference of the immunosuppression therapy, viral load, and immune status. 4 , 6 , 7 The findings of three recent publications confirmed that HIV‐positive heart transplant recipients' survival is comparable with non‐HIV‐infected patients. 8 , 9 , 10 Furthermore, the occurrences of acute rejection, chronic allograft vasculopathy, infection, and malignancy after heart transplantation (HTx) in HIV‐positive patients are also similar to general patient population. 10 Correspondingly, based on the listing criteria of the updated consensus guidelines generated by the International Society of Heart and Lung Transplantation (ISHLT), HIV infection is not considered an absolute contraindication for HTx anymore. 11 Even though, there are only a few transplant centres performing HTx in HIV‐positive patients. 6
Case report
We present a case report of a 40‐year‐old male patient with well‐controlled HIV infection in previous medical history. He was diagnosed with HIV infection in 2012, when he had cytomegalovirus infection. In the same year, he underwent opportunistic infections including perianal fistula and pneumonia leading to septic shock. Since then, HAART had been started including darunavir/cobicistat and INN‐etravirine. HIV viral load was undetectable, and CD4+ count was greater than 200 cells per microlitre for several years.
At present, the patient was first hospitalized by a district hospital due to new onset, worsening dyspnoea. The clinical examinations confirmed severely decreased left ventricular function [ejection fraction (EF): 20%, cardiac index: 1.37 L/min/m2] and a negative coronary angiography with a possible aetiology of acute viral myocarditis. Despite of 5 days of combined inotropic support, patient developed refractory cardiogenic shock; therefore, he was referred for mechanical circulatory support (MCS) implantation and transferred to our tertiary centre. On admission to the intensive care unit, the patient's clinical parameters were as follows: left ventricular EF: 14%, APACHE II score: 9 points, SOFA score: 8 points. The patient went for urgent central venoarterial extracorporeal membrane oxygenation (VA‐ECMO) implantation. Intraoperative myocardial biopsy confirmed the diagnosis of subacute active lymphocytic myocarditis, which was considered to be independent of HIV infection, according to the undetectable viral load for many years. Eosinophil granulocytes, giant cells or granulomatous inflammation were excluded. Over the first four postoperative days, the patient stabilized on VA‐ECMO support of median of 3.5 (3.4, 3.9) L/min, his vasopressor requirement decreased. On the 2nd postoperative day, the patient has been extubated uneventfully; however, 2 days later, he required an urgent reintubation due to bleeding from the respiratory tract. Laboratory tests showed thrombocytopenia (lowest platelet count: 64 g/L), and the rotational thromboelastometry (ROTEM) revealed pronounced substrate deficiency and prolonged clotting time (Figure 1 ).
Figure 1 Rotational thromboelastometry test performed at the time of the first respiratory tract bleeding on venoarterial extracorporeal membrane oxygenation support. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
Excluding any improvement or recovery in patient's cardiac function, the multidisciplinary team decided to upgrade VA‐ECMO system to paracorporeal biventricular assist device (BiVAD), which was performed 7 days after the VA‐ECMO implantation. The patient's general condition showed slow stabilization while being on BiVAD support. Based on echocardiography results, both the left and right ventricular functions remained severely deteriorated. Over the first 2 weeks after BiVAD implantation, several bleeding episodes occurred from the respiratory tract and from the exit points of the BiVAD cannulas, which were first considered the consequence of the persistent thrombocytopenia. Interestingly, ROTEM follow‐up tests showed hypercoagulable state (Figure 2 ).
Figure 2 Rotational thromboelastometry test during bleeding from the respiratory tract and from the exit points of the biventricular assist device cannulas. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
To clarify the developed complex coagulopathy, additional haematological examinations have been performed, which confirmed secondary thrombotic microangiopathy (TMA). The ADAMTS13 activity had been severely decreased; the activity of both classical and alternative complement pathways had been markedly reduced (Table 1 ). According to these results, we supposed that the cause of TMA was an MCS‐associated immune modulation combined with a consumptive coagulopathy leading to global over‐activation of the complement system. With the aim to control severe TMA, patient received regular fresh frozen plasma transfusions, which resulted in recovery of the TMA after 1 week (Table 1 ).
Table 1 Follow‐up parameters of secondary thrombotic microangiopathy
Parameter (reference range) Postoperative day
5 11 19 32
ADAMTS13 activity (67–137%) 30 29 61 31
Total complement activity (48–103 CH50/mL) 93 26 103 129
Alternative pathway activity (70–130%) 64 52 89 107
Complement 3 (0.9–1.8 g/L) 1.29 1.22 1.66 1.78
Complement 4 (0.15–0.55 g/L) 0.20 0.19 0.26 0.36
Terminal pathway activation marker SC5b‐9 (110–252 ng/mL) 335 473 261 225
Haptoglobin (0.3–2.0 g/L) 0.04 2.56 N/A N/A
Platelet (150–400 G/L) 85 147 196 139
On the 21st day of BiVAD support, the patient developed a spontaneous progressive right side haemothorax, which compromised his haemodynamics and led to transient haematological disturbance. Patient was referred for urgent cardiothoracic discussion and went for emergency right‐side thoracotomy. The operation revealed an unspecific bleeding source from the pericardial region of the visceral pleura, which was presumed to be associated to BiVAD support. Taking into account the patient's stable general condition (including intact cognitive status, minimal invasive mechanical ventilation support, well‐preserved extracardiac organ functions, undetectable HIV viral load with an absolute CD4+ of 244 cells per microlitre), the absence of recovery in cardiac function and the high risk for the recurrence of life‐threatening bleeding and/or thromboembolic complications, the multidisciplinary team decided to refer the patient for Eurotransplant high urgent status. On the 33rd day of BiVAD support, the patient was accepted to Eurotransplant high urgent waiting list. Two days later, he underwent heart transplantation (HTx) uneventfully. The histological investigation of the explanted heart also confirmed the diagnosis of active lymphocytic myocarditis. In places, granulation tissue and replacement fibrosis were identifiable as chronic signs. After the HTx, he tolerated an extended mobilization and a weaning programme on mechanical ventilation, which was completed on the 9th post‐transplant day. Two days later, the patient was emitted to the transplant cardiology ward. The maintenance immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Despite applying very low doses of tacrolimus, the trough drug levels were over the therapeutic range in the subsequent series (Figure 3 ). As tacrolimus is metabolized by the CYP3A enzymes, the patient's CYP3A status was determined, that resulted in intermediate CYP3A4 expression (1.48 × 10−6), which did not explain the extremely high tacrolimus blood concentrations. As cobicistat is a CYP3A enzyme inhibitor, we decided to switch darunavir/cobicistat to emtricitabine/tenofovir alafenamide/bictegravir. This change resulted in significant response in drug metabolism leading to subtherapeutic trough tacrolimus levels within few days (Figure 3 ). Withdrawal of darunavir/cobicistat induced an approximately seven‐fold increase in CYP3A4 expression (9.87 × 10−6), according to the follow‐up CYP3A4 expression measurement.
Figure 3 Tacrolimus trough drug levels and its applied doses during the post‐transplant period. The blue spotted line represents the daily applied tacrolimus dose (mg); the green bars represent tacrolimus trough levels (ng/mL). The red arrows display highly active antiretroviral therapy applied in the perioperative period. HAART, highly active antiretroviral therapy; TAC, tacrolimus.
The third routine endomyocardial biopsy on post‐transplant Day 26 revealed moderate acute cellular rejection (ISHLT Grade 2R) that recovered with steroid shot therapy. Echocardiography proved excellent graft function during the follow‐up period. The patient was discharged home in medically well condition 6 weeks after HTx. At that time, the patient's HIV infection was well controlled with undetectable viral load and absolute CD4+ of 270 cells per cubic millimetre. Four months after HTx, the patient is stable with outstanding general condition, excellent graft function, and without developing any post‐transplant opportunistic infections.
Discussion
Mechanical circulatory support implantation and performing HTx in HIV‐infected patients is exceptionally rare, despite the fact that prevalence of chronic heart failure is significantly higher in this patient group than in non‐HIV‐infected subjects. 3 , 4 , 5 The main challenges of the post‐transplant care are to prevent drug–drug interactions and HIV reactivation by immunosuppressants. 6 Bontempo et al. reported the first case of HTx in a HIV‐positive patient performed in the USA in 1988. 12 The first European report was published in 2011. 13 Several subsequent studies have highlighted that post‐transplant survival rates among patients with well‐controlled HIV infection and stable chronic heart failure are the same as compared with general patient population. 8 , 9 , 10 Despite these encouraging data, less than 80 HIV‐infected patients went through cardiac transplantation until the end of the year 2019. 14 To the best of our knowledge, there have been only a few case reports regarding VA‐ECMO implantation in HIV‐infected patients. In one of these cases, ECMO was upgraded to long‐term LVAD, and the patient underwent successful HTx later. 15 Another recent publication described heart‐lung transplantation bridged by VA‐ECMO in an HIV‐positive patient. 16 In comparison, experiences of VV‐ECMO implementation among HIV‐infected patients with respiratory failure are already more relevant. Favourable outcomes on the widespread use of VV‐ECMO were published by Brogan et al. and Capatos et al. according to the results of their multicentre‐based analysis and an observational study, respectively. 17 , 18 Moreover, the first case of HTx bridged by BiVAD support in an HIV‐positive patient suffering from acute heart failure was reported by Peters et al. most recently. 19 Our clinical experience demonstrates that bridge‐to‐transplant implementation of temporary MCS and performing acute HTx could be feasible and successful in HIV‐infected patients with convincing outcome, without any major complications even in case of new onset, irreversible acute heart failure.
Conflict of interest
Zsofia Szakál‐Tóth, Janos Szlavik, Adam Soltesz, Viktor Berzsenyi, Gergely Csikos, Tamas Varga, Kristof Racz, Akos Kiraly, Balazs Sax, Istvan Hartyanszky, Attila Fintha, Zoltan Prohaszka, Katalin Monostory, Bela Merkely, and Endre Nemeth declare that they have no conflicts of interest to disclose.
Consent for publication
Written informed consent was obtained from the patient for publication.
Acknowledgements
The authors would like to acknowledge Beata Nagy, MD, for participating in the histopathological investigations and Gyorgy Sinkovits, MD, for assisting in the haematological investigations. | COBICISTAT\DARUNAVIR ETHANOLATE, ETRAVIRINE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33634606 | 19,973,241 | 2021-04 |
What was the outcome of reaction 'Immunosuppressant drug level increased'? | Acute heart transplantation from mechanical circulatory support in a human immunodeficiency virus-positive patient with fulminant myocarditis.
Since the establishment of highly active antiretroviral therapy, survival rates have improved among patients with human immunodeficiency virus infection giving them the possibility to become transplant candidates. Recent publications revealed that human immunodeficiency virus-positive heart transplant recipients' survival is similar to non-infected patients. We present the case of a 40-year-old human immunodeficiency virus infected patient, who was hospitalized due to severely decreased left ventricular function with a possible aetiology of acute myocarditis, that has later been confirmed by histological investigation of myocardial biopsy. Due to rapid progression to refractory cardiogenic shock, extracorporeal membrane oxygenation implantation had been initiated, which was upgraded to biventricular assist device later. On the 35th day of upgraded support, the patient underwent heart transplantation uneventfully. Our clinical experience confirms that implementation of temporary mechanical circulatory support and subsequent cardiac transplantation might be successful in human immunodeficiency virus-positive patients even in case of new onset, irreversible acute heart failure.
Introduction
Since the establishment of highly active antiretroviral therapy (HAART), survival rates have improved among patients with human immunodeficiency virus (HIV) infection with a parallel decrease in the incidence of acquired immunodeficiency syndrome, turning HIV infection into a chronic disease. 1 , 2 Nowadays, HIV‐positive patients' life expectancy mostly depends on chronic organ dysfunctions, including chronic hepatic, renal and pulmonary disorders, or cardiomyopathy. 3 The risk of cardiovascular disease and the prevalence of chronic heart failure are significantly higher in HIV‐positive patients as compared with non‐HIV‐infected patients. 3 , 4 , 5 HIV infection had been a contraindication for solid organ transplantation until recently, due to concern about the interference of the immunosuppression therapy, viral load, and immune status. 4 , 6 , 7 The findings of three recent publications confirmed that HIV‐positive heart transplant recipients' survival is comparable with non‐HIV‐infected patients. 8 , 9 , 10 Furthermore, the occurrences of acute rejection, chronic allograft vasculopathy, infection, and malignancy after heart transplantation (HTx) in HIV‐positive patients are also similar to general patient population. 10 Correspondingly, based on the listing criteria of the updated consensus guidelines generated by the International Society of Heart and Lung Transplantation (ISHLT), HIV infection is not considered an absolute contraindication for HTx anymore. 11 Even though, there are only a few transplant centres performing HTx in HIV‐positive patients. 6
Case report
We present a case report of a 40‐year‐old male patient with well‐controlled HIV infection in previous medical history. He was diagnosed with HIV infection in 2012, when he had cytomegalovirus infection. In the same year, he underwent opportunistic infections including perianal fistula and pneumonia leading to septic shock. Since then, HAART had been started including darunavir/cobicistat and INN‐etravirine. HIV viral load was undetectable, and CD4+ count was greater than 200 cells per microlitre for several years.
At present, the patient was first hospitalized by a district hospital due to new onset, worsening dyspnoea. The clinical examinations confirmed severely decreased left ventricular function [ejection fraction (EF): 20%, cardiac index: 1.37 L/min/m2] and a negative coronary angiography with a possible aetiology of acute viral myocarditis. Despite of 5 days of combined inotropic support, patient developed refractory cardiogenic shock; therefore, he was referred for mechanical circulatory support (MCS) implantation and transferred to our tertiary centre. On admission to the intensive care unit, the patient's clinical parameters were as follows: left ventricular EF: 14%, APACHE II score: 9 points, SOFA score: 8 points. The patient went for urgent central venoarterial extracorporeal membrane oxygenation (VA‐ECMO) implantation. Intraoperative myocardial biopsy confirmed the diagnosis of subacute active lymphocytic myocarditis, which was considered to be independent of HIV infection, according to the undetectable viral load for many years. Eosinophil granulocytes, giant cells or granulomatous inflammation were excluded. Over the first four postoperative days, the patient stabilized on VA‐ECMO support of median of 3.5 (3.4, 3.9) L/min, his vasopressor requirement decreased. On the 2nd postoperative day, the patient has been extubated uneventfully; however, 2 days later, he required an urgent reintubation due to bleeding from the respiratory tract. Laboratory tests showed thrombocytopenia (lowest platelet count: 64 g/L), and the rotational thromboelastometry (ROTEM) revealed pronounced substrate deficiency and prolonged clotting time (Figure 1 ).
Figure 1 Rotational thromboelastometry test performed at the time of the first respiratory tract bleeding on venoarterial extracorporeal membrane oxygenation support. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
Excluding any improvement or recovery in patient's cardiac function, the multidisciplinary team decided to upgrade VA‐ECMO system to paracorporeal biventricular assist device (BiVAD), which was performed 7 days after the VA‐ECMO implantation. The patient's general condition showed slow stabilization while being on BiVAD support. Based on echocardiography results, both the left and right ventricular functions remained severely deteriorated. Over the first 2 weeks after BiVAD implantation, several bleeding episodes occurred from the respiratory tract and from the exit points of the BiVAD cannulas, which were first considered the consequence of the persistent thrombocytopenia. Interestingly, ROTEM follow‐up tests showed hypercoagulable state (Figure 2 ).
Figure 2 Rotational thromboelastometry test during bleeding from the respiratory tract and from the exit points of the biventricular assist device cannulas. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
To clarify the developed complex coagulopathy, additional haematological examinations have been performed, which confirmed secondary thrombotic microangiopathy (TMA). The ADAMTS13 activity had been severely decreased; the activity of both classical and alternative complement pathways had been markedly reduced (Table 1 ). According to these results, we supposed that the cause of TMA was an MCS‐associated immune modulation combined with a consumptive coagulopathy leading to global over‐activation of the complement system. With the aim to control severe TMA, patient received regular fresh frozen plasma transfusions, which resulted in recovery of the TMA after 1 week (Table 1 ).
Table 1 Follow‐up parameters of secondary thrombotic microangiopathy
Parameter (reference range) Postoperative day
5 11 19 32
ADAMTS13 activity (67–137%) 30 29 61 31
Total complement activity (48–103 CH50/mL) 93 26 103 129
Alternative pathway activity (70–130%) 64 52 89 107
Complement 3 (0.9–1.8 g/L) 1.29 1.22 1.66 1.78
Complement 4 (0.15–0.55 g/L) 0.20 0.19 0.26 0.36
Terminal pathway activation marker SC5b‐9 (110–252 ng/mL) 335 473 261 225
Haptoglobin (0.3–2.0 g/L) 0.04 2.56 N/A N/A
Platelet (150–400 G/L) 85 147 196 139
On the 21st day of BiVAD support, the patient developed a spontaneous progressive right side haemothorax, which compromised his haemodynamics and led to transient haematological disturbance. Patient was referred for urgent cardiothoracic discussion and went for emergency right‐side thoracotomy. The operation revealed an unspecific bleeding source from the pericardial region of the visceral pleura, which was presumed to be associated to BiVAD support. Taking into account the patient's stable general condition (including intact cognitive status, minimal invasive mechanical ventilation support, well‐preserved extracardiac organ functions, undetectable HIV viral load with an absolute CD4+ of 244 cells per microlitre), the absence of recovery in cardiac function and the high risk for the recurrence of life‐threatening bleeding and/or thromboembolic complications, the multidisciplinary team decided to refer the patient for Eurotransplant high urgent status. On the 33rd day of BiVAD support, the patient was accepted to Eurotransplant high urgent waiting list. Two days later, he underwent heart transplantation (HTx) uneventfully. The histological investigation of the explanted heart also confirmed the diagnosis of active lymphocytic myocarditis. In places, granulation tissue and replacement fibrosis were identifiable as chronic signs. After the HTx, he tolerated an extended mobilization and a weaning programme on mechanical ventilation, which was completed on the 9th post‐transplant day. Two days later, the patient was emitted to the transplant cardiology ward. The maintenance immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Despite applying very low doses of tacrolimus, the trough drug levels were over the therapeutic range in the subsequent series (Figure 3 ). As tacrolimus is metabolized by the CYP3A enzymes, the patient's CYP3A status was determined, that resulted in intermediate CYP3A4 expression (1.48 × 10−6), which did not explain the extremely high tacrolimus blood concentrations. As cobicistat is a CYP3A enzyme inhibitor, we decided to switch darunavir/cobicistat to emtricitabine/tenofovir alafenamide/bictegravir. This change resulted in significant response in drug metabolism leading to subtherapeutic trough tacrolimus levels within few days (Figure 3 ). Withdrawal of darunavir/cobicistat induced an approximately seven‐fold increase in CYP3A4 expression (9.87 × 10−6), according to the follow‐up CYP3A4 expression measurement.
Figure 3 Tacrolimus trough drug levels and its applied doses during the post‐transplant period. The blue spotted line represents the daily applied tacrolimus dose (mg); the green bars represent tacrolimus trough levels (ng/mL). The red arrows display highly active antiretroviral therapy applied in the perioperative period. HAART, highly active antiretroviral therapy; TAC, tacrolimus.
The third routine endomyocardial biopsy on post‐transplant Day 26 revealed moderate acute cellular rejection (ISHLT Grade 2R) that recovered with steroid shot therapy. Echocardiography proved excellent graft function during the follow‐up period. The patient was discharged home in medically well condition 6 weeks after HTx. At that time, the patient's HIV infection was well controlled with undetectable viral load and absolute CD4+ of 270 cells per cubic millimetre. Four months after HTx, the patient is stable with outstanding general condition, excellent graft function, and without developing any post‐transplant opportunistic infections.
Discussion
Mechanical circulatory support implantation and performing HTx in HIV‐infected patients is exceptionally rare, despite the fact that prevalence of chronic heart failure is significantly higher in this patient group than in non‐HIV‐infected subjects. 3 , 4 , 5 The main challenges of the post‐transplant care are to prevent drug–drug interactions and HIV reactivation by immunosuppressants. 6 Bontempo et al. reported the first case of HTx in a HIV‐positive patient performed in the USA in 1988. 12 The first European report was published in 2011. 13 Several subsequent studies have highlighted that post‐transplant survival rates among patients with well‐controlled HIV infection and stable chronic heart failure are the same as compared with general patient population. 8 , 9 , 10 Despite these encouraging data, less than 80 HIV‐infected patients went through cardiac transplantation until the end of the year 2019. 14 To the best of our knowledge, there have been only a few case reports regarding VA‐ECMO implantation in HIV‐infected patients. In one of these cases, ECMO was upgraded to long‐term LVAD, and the patient underwent successful HTx later. 15 Another recent publication described heart‐lung transplantation bridged by VA‐ECMO in an HIV‐positive patient. 16 In comparison, experiences of VV‐ECMO implementation among HIV‐infected patients with respiratory failure are already more relevant. Favourable outcomes on the widespread use of VV‐ECMO were published by Brogan et al. and Capatos et al. according to the results of their multicentre‐based analysis and an observational study, respectively. 17 , 18 Moreover, the first case of HTx bridged by BiVAD support in an HIV‐positive patient suffering from acute heart failure was reported by Peters et al. most recently. 19 Our clinical experience demonstrates that bridge‐to‐transplant implementation of temporary MCS and performing acute HTx could be feasible and successful in HIV‐infected patients with convincing outcome, without any major complications even in case of new onset, irreversible acute heart failure.
Conflict of interest
Zsofia Szakál‐Tóth, Janos Szlavik, Adam Soltesz, Viktor Berzsenyi, Gergely Csikos, Tamas Varga, Kristof Racz, Akos Kiraly, Balazs Sax, Istvan Hartyanszky, Attila Fintha, Zoltan Prohaszka, Katalin Monostory, Bela Merkely, and Endre Nemeth declare that they have no conflicts of interest to disclose.
Consent for publication
Written informed consent was obtained from the patient for publication.
Acknowledgements
The authors would like to acknowledge Beata Nagy, MD, for participating in the histopathological investigations and Gyorgy Sinkovits, MD, for assisting in the haematological investigations. | Recovered | ReactionOutcome | CC BY-NC-ND | 33634606 | 19,973,241 | 2021-04 |
What was the outcome of reaction 'Transplant rejection'? | Acute heart transplantation from mechanical circulatory support in a human immunodeficiency virus-positive patient with fulminant myocarditis.
Since the establishment of highly active antiretroviral therapy, survival rates have improved among patients with human immunodeficiency virus infection giving them the possibility to become transplant candidates. Recent publications revealed that human immunodeficiency virus-positive heart transplant recipients' survival is similar to non-infected patients. We present the case of a 40-year-old human immunodeficiency virus infected patient, who was hospitalized due to severely decreased left ventricular function with a possible aetiology of acute myocarditis, that has later been confirmed by histological investigation of myocardial biopsy. Due to rapid progression to refractory cardiogenic shock, extracorporeal membrane oxygenation implantation had been initiated, which was upgraded to biventricular assist device later. On the 35th day of upgraded support, the patient underwent heart transplantation uneventfully. Our clinical experience confirms that implementation of temporary mechanical circulatory support and subsequent cardiac transplantation might be successful in human immunodeficiency virus-positive patients even in case of new onset, irreversible acute heart failure.
Introduction
Since the establishment of highly active antiretroviral therapy (HAART), survival rates have improved among patients with human immunodeficiency virus (HIV) infection with a parallel decrease in the incidence of acquired immunodeficiency syndrome, turning HIV infection into a chronic disease. 1 , 2 Nowadays, HIV‐positive patients' life expectancy mostly depends on chronic organ dysfunctions, including chronic hepatic, renal and pulmonary disorders, or cardiomyopathy. 3 The risk of cardiovascular disease and the prevalence of chronic heart failure are significantly higher in HIV‐positive patients as compared with non‐HIV‐infected patients. 3 , 4 , 5 HIV infection had been a contraindication for solid organ transplantation until recently, due to concern about the interference of the immunosuppression therapy, viral load, and immune status. 4 , 6 , 7 The findings of three recent publications confirmed that HIV‐positive heart transplant recipients' survival is comparable with non‐HIV‐infected patients. 8 , 9 , 10 Furthermore, the occurrences of acute rejection, chronic allograft vasculopathy, infection, and malignancy after heart transplantation (HTx) in HIV‐positive patients are also similar to general patient population. 10 Correspondingly, based on the listing criteria of the updated consensus guidelines generated by the International Society of Heart and Lung Transplantation (ISHLT), HIV infection is not considered an absolute contraindication for HTx anymore. 11 Even though, there are only a few transplant centres performing HTx in HIV‐positive patients. 6
Case report
We present a case report of a 40‐year‐old male patient with well‐controlled HIV infection in previous medical history. He was diagnosed with HIV infection in 2012, when he had cytomegalovirus infection. In the same year, he underwent opportunistic infections including perianal fistula and pneumonia leading to septic shock. Since then, HAART had been started including darunavir/cobicistat and INN‐etravirine. HIV viral load was undetectable, and CD4+ count was greater than 200 cells per microlitre for several years.
At present, the patient was first hospitalized by a district hospital due to new onset, worsening dyspnoea. The clinical examinations confirmed severely decreased left ventricular function [ejection fraction (EF): 20%, cardiac index: 1.37 L/min/m2] and a negative coronary angiography with a possible aetiology of acute viral myocarditis. Despite of 5 days of combined inotropic support, patient developed refractory cardiogenic shock; therefore, he was referred for mechanical circulatory support (MCS) implantation and transferred to our tertiary centre. On admission to the intensive care unit, the patient's clinical parameters were as follows: left ventricular EF: 14%, APACHE II score: 9 points, SOFA score: 8 points. The patient went for urgent central venoarterial extracorporeal membrane oxygenation (VA‐ECMO) implantation. Intraoperative myocardial biopsy confirmed the diagnosis of subacute active lymphocytic myocarditis, which was considered to be independent of HIV infection, according to the undetectable viral load for many years. Eosinophil granulocytes, giant cells or granulomatous inflammation were excluded. Over the first four postoperative days, the patient stabilized on VA‐ECMO support of median of 3.5 (3.4, 3.9) L/min, his vasopressor requirement decreased. On the 2nd postoperative day, the patient has been extubated uneventfully; however, 2 days later, he required an urgent reintubation due to bleeding from the respiratory tract. Laboratory tests showed thrombocytopenia (lowest platelet count: 64 g/L), and the rotational thromboelastometry (ROTEM) revealed pronounced substrate deficiency and prolonged clotting time (Figure 1 ).
Figure 1 Rotational thromboelastometry test performed at the time of the first respiratory tract bleeding on venoarterial extracorporeal membrane oxygenation support. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
Excluding any improvement or recovery in patient's cardiac function, the multidisciplinary team decided to upgrade VA‐ECMO system to paracorporeal biventricular assist device (BiVAD), which was performed 7 days after the VA‐ECMO implantation. The patient's general condition showed slow stabilization while being on BiVAD support. Based on echocardiography results, both the left and right ventricular functions remained severely deteriorated. Over the first 2 weeks after BiVAD implantation, several bleeding episodes occurred from the respiratory tract and from the exit points of the BiVAD cannulas, which were first considered the consequence of the persistent thrombocytopenia. Interestingly, ROTEM follow‐up tests showed hypercoagulable state (Figure 2 ).
Figure 2 Rotational thromboelastometry test during bleeding from the respiratory tract and from the exit points of the biventricular assist device cannulas. A5, amplitude 5 min after CT; A10, amplitude 10 min after CT; A20, amplitude 20 min after CT; A30, amplitude 30 min after CT; CFT, clot formation time; CT, clotting time.
To clarify the developed complex coagulopathy, additional haematological examinations have been performed, which confirmed secondary thrombotic microangiopathy (TMA). The ADAMTS13 activity had been severely decreased; the activity of both classical and alternative complement pathways had been markedly reduced (Table 1 ). According to these results, we supposed that the cause of TMA was an MCS‐associated immune modulation combined with a consumptive coagulopathy leading to global over‐activation of the complement system. With the aim to control severe TMA, patient received regular fresh frozen plasma transfusions, which resulted in recovery of the TMA after 1 week (Table 1 ).
Table 1 Follow‐up parameters of secondary thrombotic microangiopathy
Parameter (reference range) Postoperative day
5 11 19 32
ADAMTS13 activity (67–137%) 30 29 61 31
Total complement activity (48–103 CH50/mL) 93 26 103 129
Alternative pathway activity (70–130%) 64 52 89 107
Complement 3 (0.9–1.8 g/L) 1.29 1.22 1.66 1.78
Complement 4 (0.15–0.55 g/L) 0.20 0.19 0.26 0.36
Terminal pathway activation marker SC5b‐9 (110–252 ng/mL) 335 473 261 225
Haptoglobin (0.3–2.0 g/L) 0.04 2.56 N/A N/A
Platelet (150–400 G/L) 85 147 196 139
On the 21st day of BiVAD support, the patient developed a spontaneous progressive right side haemothorax, which compromised his haemodynamics and led to transient haematological disturbance. Patient was referred for urgent cardiothoracic discussion and went for emergency right‐side thoracotomy. The operation revealed an unspecific bleeding source from the pericardial region of the visceral pleura, which was presumed to be associated to BiVAD support. Taking into account the patient's stable general condition (including intact cognitive status, minimal invasive mechanical ventilation support, well‐preserved extracardiac organ functions, undetectable HIV viral load with an absolute CD4+ of 244 cells per microlitre), the absence of recovery in cardiac function and the high risk for the recurrence of life‐threatening bleeding and/or thromboembolic complications, the multidisciplinary team decided to refer the patient for Eurotransplant high urgent status. On the 33rd day of BiVAD support, the patient was accepted to Eurotransplant high urgent waiting list. Two days later, he underwent heart transplantation (HTx) uneventfully. The histological investigation of the explanted heart also confirmed the diagnosis of active lymphocytic myocarditis. In places, granulation tissue and replacement fibrosis were identifiable as chronic signs. After the HTx, he tolerated an extended mobilization and a weaning programme on mechanical ventilation, which was completed on the 9th post‐transplant day. Two days later, the patient was emitted to the transplant cardiology ward. The maintenance immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and methylprednisolone. Despite applying very low doses of tacrolimus, the trough drug levels were over the therapeutic range in the subsequent series (Figure 3 ). As tacrolimus is metabolized by the CYP3A enzymes, the patient's CYP3A status was determined, that resulted in intermediate CYP3A4 expression (1.48 × 10−6), which did not explain the extremely high tacrolimus blood concentrations. As cobicistat is a CYP3A enzyme inhibitor, we decided to switch darunavir/cobicistat to emtricitabine/tenofovir alafenamide/bictegravir. This change resulted in significant response in drug metabolism leading to subtherapeutic trough tacrolimus levels within few days (Figure 3 ). Withdrawal of darunavir/cobicistat induced an approximately seven‐fold increase in CYP3A4 expression (9.87 × 10−6), according to the follow‐up CYP3A4 expression measurement.
Figure 3 Tacrolimus trough drug levels and its applied doses during the post‐transplant period. The blue spotted line represents the daily applied tacrolimus dose (mg); the green bars represent tacrolimus trough levels (ng/mL). The red arrows display highly active antiretroviral therapy applied in the perioperative period. HAART, highly active antiretroviral therapy; TAC, tacrolimus.
The third routine endomyocardial biopsy on post‐transplant Day 26 revealed moderate acute cellular rejection (ISHLT Grade 2R) that recovered with steroid shot therapy. Echocardiography proved excellent graft function during the follow‐up period. The patient was discharged home in medically well condition 6 weeks after HTx. At that time, the patient's HIV infection was well controlled with undetectable viral load and absolute CD4+ of 270 cells per cubic millimetre. Four months after HTx, the patient is stable with outstanding general condition, excellent graft function, and without developing any post‐transplant opportunistic infections.
Discussion
Mechanical circulatory support implantation and performing HTx in HIV‐infected patients is exceptionally rare, despite the fact that prevalence of chronic heart failure is significantly higher in this patient group than in non‐HIV‐infected subjects. 3 , 4 , 5 The main challenges of the post‐transplant care are to prevent drug–drug interactions and HIV reactivation by immunosuppressants. 6 Bontempo et al. reported the first case of HTx in a HIV‐positive patient performed in the USA in 1988. 12 The first European report was published in 2011. 13 Several subsequent studies have highlighted that post‐transplant survival rates among patients with well‐controlled HIV infection and stable chronic heart failure are the same as compared with general patient population. 8 , 9 , 10 Despite these encouraging data, less than 80 HIV‐infected patients went through cardiac transplantation until the end of the year 2019. 14 To the best of our knowledge, there have been only a few case reports regarding VA‐ECMO implantation in HIV‐infected patients. In one of these cases, ECMO was upgraded to long‐term LVAD, and the patient underwent successful HTx later. 15 Another recent publication described heart‐lung transplantation bridged by VA‐ECMO in an HIV‐positive patient. 16 In comparison, experiences of VV‐ECMO implementation among HIV‐infected patients with respiratory failure are already more relevant. Favourable outcomes on the widespread use of VV‐ECMO were published by Brogan et al. and Capatos et al. according to the results of their multicentre‐based analysis and an observational study, respectively. 17 , 18 Moreover, the first case of HTx bridged by BiVAD support in an HIV‐positive patient suffering from acute heart failure was reported by Peters et al. most recently. 19 Our clinical experience demonstrates that bridge‐to‐transplant implementation of temporary MCS and performing acute HTx could be feasible and successful in HIV‐infected patients with convincing outcome, without any major complications even in case of new onset, irreversible acute heart failure.
Conflict of interest
Zsofia Szakál‐Tóth, Janos Szlavik, Adam Soltesz, Viktor Berzsenyi, Gergely Csikos, Tamas Varga, Kristof Racz, Akos Kiraly, Balazs Sax, Istvan Hartyanszky, Attila Fintha, Zoltan Prohaszka, Katalin Monostory, Bela Merkely, and Endre Nemeth declare that they have no conflicts of interest to disclose.
Consent for publication
Written informed consent was obtained from the patient for publication.
Acknowledgements
The authors would like to acknowledge Beata Nagy, MD, for participating in the histopathological investigations and Gyorgy Sinkovits, MD, for assisting in the haematological investigations. | Recovered | ReactionOutcome | CC BY-NC-ND | 33634606 | 19,973,241 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple-drug resistance'. | Paraneoplastic Encephalitis Associated with Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.
Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.
INTRODUCTION
Paraneoplastic neurologic diseases (PND) including limbic encephalitis (LE) have been reported to occur in association with breast cancer for many decades, although its incidence is quite rare [1]. Breast cancer-related neurologic paraneoplastic syndromes can have diverse presentations, including sensory and motor-type neuropathies, paraneoplastic cerebellar degeneration (PCD), opsoclonus-myoclonus syndrome, stiff person syndrome, encephalomyelitis, and paraneoplastic retinopathy [1]. Because breast cancer-related paraneoplastic syndromes are uncommon, only limited data are available to support their association with specific breast cancer subsets, presence of certain histological subtypes, advanced clinical stage, or lymphovascular invasion [1].
The diagnosis of a paraneoplastic neurological disorder requires the presence of neurological symptoms, diagnosis of cancer within 4 years, exclusion of other neurological disorders, and at least one of the following findings: cerebrospinal fluid (CSF) analysis showing inflammation with negative cytology, brain magnetic resonance imaging (MRI) demonstrating characteristic hyperintensity signals on T2-weighted fluid attenuated inversion recovery images of the medial temporal lobe(s), or epileptic activity in the temporal lobes by electroencephalogram (EEG) [12]. The presence of autoantibodies in the blood or CSF is not necessary for diagnosis. Interestingly, neuron-specific autoantibodies are only found in approximately 60%–70% of patients with clinically diagnosed paraneoplastic syndromes associated with breast cancer [1]. Therefore, antibody testing may be helpful if positive, but the absence of antibodies cannot rule out paraneoplastic neurologic syndrome [1].
Herein, we report a unique case of a patient who presented with rapid-onset altered mental status and temporal lobe seizures along with no other obvious neurologic disorder based on extensive imaging as well as CSF and serum analyses in the setting of a new diagnosis of locally advanced hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
CASE REPORT
A 56-year-old woman was admitted to the hospital for psychosis, paranoia, hallucinations, and seizures. Two months before admission, she presented to her primary care physician with right upper extremity numbness and an MRI of the cervical spine that revealed degenerative disc disease. During the following weeks, she developed paranoia, psychosis, and hallucinations, leading to admission at a psychiatric facility. According to the evaluation and treatment of her psychiatric symptoms, the patient was transferred to a medical facility for further workup and to rule out organic causes.
Her past medical history included insomnia treated with zolpidem, but no prior psychiatric disorder. Surgical history was notable for left knee arthroscopy. Her family history included Alzheimer's dementia in her father and a brain tumor in her mother. The patient was living independently and was working before admission. She was a former smoker who did not consume alcohol, marijuana, or other drugs.
On initial presentation to the medical facility, EEG demonstrated focal subclinical seizures originating from the left temporal region. Continuous EEG confirmed frequent seizures, and she was started on multiple anti-epileptic drugs (AEDs), including fosphenytoin, phenytoin, lacosamide, divalproex, and levetiracetam. Her seizures were refractory to medical therapy, and the patient required intubation for airway protection. Brain MRI demonstrated no acute intracranial findings, including no findings specific for encephalitis but incidentally revealed a small right superior frontoparietal paramedian meningioma. Infectious workup, toxicology, blood counts, and electrolytes were all within normal limits, and we could not identify a cause for her seizures and changes in mental status. Computed tomography (CT) of the chest, abdomen, and pelvis revealed a 2.5-cm mass in the right breast with associated right axillary lymphadenopathy and no evidence of distant metastatic disease. Diagnostic lumbar puncture was performed and CSF analysis revealed a cell count of 4 white blood cells (WBC) (reference range, < 5 WBC), 324 red blood cells, glucose 59 mg/dL (reference range, < 300 mg/dL), protein 49 mg/dL (reference range, 18–58 mg/dL), oligoclonal bands, and elevated immunoglobulin G (IgG) index. A second CSF sample was obtained several days later and showed similar findings, and viral, bacterial, and fungal cultures were negative. Cytology was negative for malignant cells in both samples. A comprehensive serum paraneoplastic autoantibody panel and a CSF autoimmune epilepsy panel were both negative for autoantibodies (Table 1). However, the staining pattern was suggestive of the presence of an unknown neuron-specific autoantibody.
Table 1 Comprehensive paraneoplastic autoantibody and autoimmune epilepsy work-up
Serum paraneoplastic autoantibodies CSF autoimmune epilepsy labs
Test Result (reference value) Test Result (reference value)
ANNA-1 (Hu) Negative (< 1:240 titer) NMDA-R AB CBA Negative (negative)
ANNA-2 (Ri) Negative (< 1:240 titer) VGKC Complex AB IPA 0 (≤ 0.02 nmol/L)
ANNA-3 Negative (< 1:240 titer) LGI1-IgG CBA Negative (negative)
AGNA-1 Negative (< 1:240 titer) CASPR2-IgG CBA Negative (negative)
PCA-1 (Yo) Negative (< 1:240 titer) GAD65 AB Assay 0 (≤ 0.02 nmol/L)
PCA-2 Negative (< 1:240 titer) GABA-B-R AB CBA Negative (negative)
PCA-Tr Negative (< 1:240 titer) AMPA-R AB CBA Negative (negative)
Amphiphysin AB Negative (< 1:240 titer) ANNA-1 Negative (< 1:2 titer)
CRMP-5-IgG Negative (< 1:240 titer) ANNA-2 Negative (< 1:2 titer)
P/Q CAL CHAN AB 0.01 (≤ 0.02 nmol/L) ANNA-3 Negative (< 1:2 titer)
N-CAL CHAN AB 0 (≤ 0.03 nmol/L) AGNA-1 Negative (< 1:2 titer)
ACHR GANG NEUR AB 0 (≤ 0.02 nmol/L) PCA-2 Negative (< 1:2 titer)
NEUR K CHAN AB 0 (≤ 0.02 nmol/L) PCA-Tr Negative (< 1:2 titer)
STRIATIONAL AB Negative (< 1:240 titer) Amphiphysin AB Negative (< 1:2 titer)
CRMP-5-IgG Negative (< 1:2 titer)
CSF = cerebrospinal fluid; ANNA = anti-neuronal nuclear antibody; AGNA = anti-glial nuclear antibody; PCA = Purkinje cell cytoplasmic antibody; AB = antibody; CRMP-5 = collapsin response-mediator protein-5; IgG = immunoglobulin G; P/Q CAL CHAN = P/Q-type calcium channel; N-CAL CHAN = N-type calcium channel; ACHR GANG NEUR = acetylcholine receptor ganglionic neuronal; NEUR K = neuronal potassium channel; NMDA-R = N-methyl-d-aspartate receptor; CBA = collagen-binding activity; VGKC Complex AB IPA = neuronal voltage-gated potassium channel antibody; LGI1 = leucine-rich gliomainactivated 1; CASPR2 = contactin-associated protein-like 2; GAD65= glutamic acid decarboxylase; GABA-B-R = gamma aminobutyric acid receptor type B; AMPA-R = AMPA receptor.
The patient underwent biopsy of the right breast mass, which revealed invasive ductal carcinoma, grade 3, Ki-67 90%, estrogen receptor and progesterone receptor negative by immunohistochemical staining (IHC), HER2 equivocal with focal 2+ positivity by IHC, and positive with a HER2/CEN17 signal ratio of 3.2 by fluorescent in situ hybridization. The patient was diagnosed with American Joint Committee on Cancer anatomic stage IIB (cT2N1M0) HR-negative, HER2-positive breast cancer.
Given that paraneoplastic encephalitis is concerning in the setting of a new cancer diagnosis, she received empiric steroids and intravenous immunoglobulin (IVIG) with improvement in her seizures, allowing extubation. Her AEDs were weaned to lacosamide 200 mg twice daily and levetiracetam 1,500 mg twice daily, and she was later discharged from the hospital with neurology and oncology follow-up to receive breast cancer treatment.
Unfortunately, the patient experienced increased seizures shortly after hospital discharge and was admitted to the neurology service at our tertiary referral center with presumed paraneoplastic encephalitis. Plasma-exchange was initiated, and oncology was consulted for assistance in inpatient management. Physical examination revealed that the woman had anxiety and appeared her stated age of 56; a firm, non-tender, 3-cm mobile mass was palpated in her superior right breast with no overlying skin changes; a 3-cm firm right axillary lymph node was palpated. Neurologically, the patient was oriented appropriately and did not have any focal sensory or motor deficits. She had impaired short-term memory, word-finding difficulty, intermittent non-sensical speech, and paranoia. Repeat brain MRI demonstrated edema and abnormal enhancement involving the left mesial temporal lobe, predominantly in the amygdala (Figure 1). This finding was suggestive of paraneoplastic LE in the clinical context. A CT scan of the chest, abdomen, and pelvis again demonstrated a known right breast cancer with regional axillary lymphadenopathy without evidence of distant metastatic disease (Figure 2). Given these findings, she was diagnosed with LE, a PND, most likely related to her newly diagnosed stage IIB HR-negative HER2-positive breast cancer.
Figure 1 Brain magnetic resonance imaging with and without a contrast agent upon admission to our tertiary care facility. The image demonstrates edema and abnormal enhancement involving the left mesial temporal lobe, predominantly the amygdala, suggestive of paraneoplastic encephalitis given the clinical context.
Figure 2 CT of the chest, abdomen, and pelvis. (A) Chest CT image showing right axillary lymphadenopathy and (B) tumor in the lateral right breast with central calcification.
CT = computed tomography.
Although non-metastatic breast cancer is almost always treated in the outpatient setting, the patient required inpatient treatment because her breast cancer was felt to be the most likely underlying cause of her LE, and her ongoing psychosis and seizures made discharge unsafe. Following discussion in our multidisciplinary breast cancer tumor board, the patient received one dose of trastuzumab and pertuzumab (HP) followed by right mastectomy and axillary lymph node dissection. The final pathology revealed a 2.7-cm invasive micropapillary carcinoma, grade 3, HR-negative HER2-positive (3+ by IHC) in the right breast, and 6 of 7 positive axillary lymph nodes correlated with pathologic AJCC anatomic Stage IIIA (pT2N2M0) (Figure 3). Neuroendocrine markers were not assessed on the pathological specimen, and the specimens were not assessed specifically for the presence of tumor-infiltrating cells. Within a week of her surgery, she experienced enough improvement in her encephalitis, allowing discharge to a memory care facility under 24-hour supervision. She was able to receive adjuvant chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) for 6 cycles. During this time, she experienced no deterioration of neurological symptoms but rather had consistent improvement in her mental status. By the end of the 6 cycles of TCHP, her quality of life improved and she no longer required 24-hour supervision. Interestingly, her long-term memory remained relatively intact despite continued difficulty with short-term memory, including remembering day-to-day events and tasks.
Figure 3 Tissue obtained during initial lymph node dissection. (A) Invasive ductal carcinoma at 40× magnification on hematoxylin and eosin staining, and (B) invasive ductal carcinoma with human epidermal growth factor receptor 2-staining (brown) at 40× magnification.
Upon completion of adjuvant chemotherapy, she was referred for radiation oncology considering post-mastectomy chest wall radiation provided to multiple positive lymph nodes. Unfortunately, on CT, she was found to have an enlarged, abnormal axillary lymph node, which, when biopsied, showed metastatic breast cancer that was morphologically consistent with her primary tumor (Figure 4). PET/CT was performed for re-staging and demonstrated right axillary adenopathy, but there was no other evidence of metastatic disease (Figure 5). As a result, she underwent repeat axillary lymph node dissection with 3 of 3 positive lymph nodes with extracapsular extension. This was followed by adjuvant radiation to the chest wall and regional lymph nodes. Given her persistent disease after TCHP, the patient was transitioned to adjuvant ado-trastuzumab emtansine in accordance with the KATHERINE trial [3]. Over the course of this treatment, her mental status slowly improved, brain MRIs normalized (Figure 6), and she remained seizure-free. She currently continues to experience deficits in her short-term memory; however, she is able to manage her day-to-day tasks independently.
Figure 4 Radiation simulation computed tomography scan. Persistent right axillary lymphadenopathy is indicated with an arrow.
Figure 5 Re-staging positron emission tomography-computed tomography. The image shows a rounded right axillary lymph node (9 mm × 8 mm) demonstrating no abnormal uptake and slightly increased size before the examination (7 mm × 6 mm).
Figure 6 Change in brain MRI findings over time. (A, B) Outpatient follow-up brain MRIs at 5 months from treatment initiation. Since prior, significant improvement in T2 fluid attenuated inversion recovery medial temporal signal abnormality with decreased edema. Minimal signal abnormality involves the bilateral amygdalae. MRI findings suggest improved limbic encephalitis compared to that in two previous MRI studies. (C) Resolved abnormal signal involving the mesial temporal lobes, 9 months from the initiation of treatment.
MRI = magnetic resonance imaging.
DISCUSSION
This patient met all four criteria for the diagnosis of a paraneoplastic neurological disorder, with her mental status changes associated with temporal lobe seizures, a new diagnosis of breast cancer, exclusion of other neurologic disorders with extensive imaging and serum and CSF analyses, and temporal lobe changes on MRI. Her presentation was consistent with LE, and her response to breast cancer treatment also strongly suggests a PND related to newly diagnosed, locally advanced HR-negative, HER2-positive breast cancer.
PNDs are likely initiated as an immune response directed against autoantigens expressed in tumors. Initially, immune cell priming occurs in the tumor microenvironment, as tumor-associated neoepitopes are recognized as foreign by the immune system [1]. The increased cellular proliferation and necrosis that occur in the tumor microenvironment facilitate the expression previously “hidden” neoantigens. Proteinaceous cellular debris may be scavenged by dendritic cells and carried to lymph nodes and lymphoid organs, leading to the amplification of the anti-tumor immune response in B and T cells [1]. In the setting of PND, these exposed tumor-associated neoantigens may be structurally similar to neuronal proteins, leading to an antiauto-neuroantigen response, culminating in autoimmune or paraneoplastic syndromes [1]. In this clinical situation, antineuronal antibodies can often be found in both the serum and the CSF in patients with PND. Additionally, target paraneoplastic antigens are often expressed in both the implicated tumor and the affected parts of the nervous system [1].
Several histological and laboratory findings suggest and support immune-mediated pathology for PND. Autopsy and biopsy specimens obtained from the nervous system in patients with PND typically show neuronal loss in the affected areas associated with infiltration by B cells and CD4+ T-helper cells in the perivascular spaces and infiltration of cytotoxic CD8+ T cells in the interstitial spaces [1]. CSF examination often demonstrates increased nucleated cells, oligoclonal bands, and intrathecal IgG synthesis, consistent with an inflammatory or immune-mediated process [1]. Furthering our understanding of the pathogenesis of PND has been the advent and widespread use of immune checkpoint blockade. One would hypothesize that this class of medication is very active against tumors underlying PND, which are often densely infiltrated with tumor-infiltrating lymphocytes, but they have unfortunately been repeatedly reported to worsen or even initially reveal PND. In support of an immune-mediated process, tumors associated with PND are often small [1]. In some instances, a tumor may not exist at all in the case of spontaneous remissions at the time of neurological presentations, suggesting that some PND without a detectable tumor may actually result from an immune-mediated elimination of the primary tumor [1]. In such circumstances, one could argue that CNS dysfunction actually reflects an effective immune response to systemic cancer [1].
The pathogenic role of paraneoplastic antibodies has been proven for those that are directed against easily accessible antigens located at the cell surface, allowing antineuronal antibodies to interfere with neuronal signaling or synaptic transmission. However, it is more difficult to explain the pathogenic role of antibodies directed against intracellularly located paraneoplastic antigens such as the Yo antigen in the cytoplasm, or the Hu and Ri antigens found in the nucleus. In these instances, the cellular immune response to these antigens through cytotoxic T cells is likely responsible for the neurological damage [1]. Experimental models and analyses of autopsied and biopsied tissues suggest that CD8+ cytotoxic T cells are at the core of PNDs for which the antigens of pathogenic antibodies are within the cell [1]. While intracellular antigens are not readily accessible to an immune incursion, peptides from intracellular proteins are displayed on major histocompatibility complex class I molecules, which are then available to peptide-specific cytotoxic T cells [1]. It stands to reason then that antibodies targeting intracellular antigens, which can be found in the serum and CSF, are not pathogenic, but rather are markers of a T cell-effected neuronal damage process [1].
The most common anti-neuronal antibodies in paraneoplastic LE are anti-Hu (ANNA-1), followed by anti-Ta (PNMA2) and anti-Ma (PNMA1/2) [4]. The most common anti-neuronal autoantibodies seen in patients with breast cancers are anti-Yo (Purkinje cell cytoplasmic antibody type 1), amphiphysin-IgG, and anti-Ri (ANNA-2) [2]. PND associated with HER2-positive breast cancers, which account for approximately 15% of all breast cancer diagnoses, have almost exclusively been reported to have anti-Yo antibodies [5]. Rojas-Marcos et al. [5] published a retrospective review of 27 patients with breast cancer and anti-Yo antibodies, assessing HER2-positivity, which was found in 26 (96.3%) of them, whereas only 2 of 19 (10.5%) patients with anti-Ri-associated PND were found to be HER2-positive. A thorough review of the literature reveals several case reports reporting PNDs in HER2-positive breast cancer, the majority of which are locally advanced, have anti-Yo antibodies, and are classified as PCD (Table 2). We were unable to find any prior reports of HER2-positive breast cancer with associated LE. In reviewing Murphy et al's [2] series of 56 breast cancer patients with PND, the majority of patients had stage II disease (26 patients, 46.4%), but no patients had HR-negative, HER2-positive breast cancer, and only 1 patient had a previously undefined anti-neuronal antibody, which resulted in cerebellar ataxia and peripheral neuropathy. To the best of our knowledge, our patient represents the first documented case of a HER2-positive breast cancer underlying paraneoplastic LE. It also represents a unique case in the presence of an anti-neural antibody associated with this breast cancer subtype that is rare enough that it has not been further classified or accepted into the standard paraneoplastic neurological autoimmune workup.
Table 2 Case reports detailing HER2-positive breast cancer PNDs
Reference HR/HER2 status Histology Stage Antineuronal antibody present PND syndrome
Olmez et al. [6] HR+/HER2+ IDC IIA Anti-Ri Opsoclonus
Myoclonus
Le May et al. [7] HR−/HER2+ IDC IIB Anti-Yo PCD
Dalmau et al. [8] HR−/HER2+ IDC IIA Anti-Yo PCD
Diamanti et al. [9] HR+/HER2+ IDC IIIC None LMND
Ogita et al. [10] HR−/HER2+ IDC IIIC Anti-Yo PCD
Dorn et al. [11] HR−/HER2+ IDC IIIA Anti-Yo PCD
Rupasinghe and Butler [12] Unknown HR/HER2+ Poorly differentiated adenocarcinoma IIA Anti-Yo PCD
Frings et al. [13] HR−/HER2+ ILC IIIB Anti-Yo PCD
Sancho et al. [14] HR+/HER2+ IDC IIB Anti-Yo PCD
HER2 = human epidermal growth factor receptor 2; PND = paraneoplastic neurologic disorder; HR = hormone receptor; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; PCD = paraneoplastic cerebellar degeneration; LMND = lower motor neuron disease.
The most effective therapy for cancer-related PND is the treatment of the underlying malignancy. Gultekin et al. [4] reported 50 patients with PND, including four with breast cancer, showing that treatment of the tumor was more effective in improving neurological outcomes than the use of immunosuppression. Improvement was observed in 38% of anti-Hu patients, 30% of anti-Ta patients, and 64% of patients without these antibodies [4]. In a separate case series, Candler et al. [15] reported that 14% of patients (9/64) with PND had an associated breast cancer (of unknown subtype) and that the only treatment that led to improvement or stabilization of neurologic function was cancer treatment. Aside from cancer therapy, numerous treatment modalities have been investigated in PND and have been found to have limited efficacy. Despite this, immunosuppressive therapy is often used as a bridge to more definitive anticancer therapy. This is especially the case in patients diagnosed with PND as the first symptom of malignancy and before a formal diagnosis. Unfortunately, most patients with PND do not achieve full recovery even with anticancer therapy, and treatment of the underlying malignancy in PND can often stabilize only neurological symptoms, rather than lead to consistent long-term improvements. Finally, the prognosis of PND remains poor, and generally, any level of stabilization or improvement in neurologic symptoms that occurs within the first few months of diagnosis, and treatment becomes a new baseline for these patients.
While our patient initially had slight transient improvements with immunosuppression in the form of IVIG, steroids, and plasma exchange, real improvement was not seen until she underwent surgical resection and began receiving systemic therapy. The decision to proceed with surgical resection upfront as compared to initiating neoadjuvant chemotherapy with TCHP immediately was challenging. Our usual standard of care would be to proceed with neoadjuvant chemotherapy in the setting of node-positive, HER2-positive breast cancer. This approach can often lead to breast-conserving surgery and may even downstage the axilla, allowing for sentinel lymph node biopsy rather than axillary lymph node dissection in select patients. The use of neoadjuvant chemotherapy also allows the use of pathologic complete response as a prognostic marker that strongly correlated with improved disease-free and overall survival and tailoring adjuvant HER2-directed therapy based on response.
In our patient, however, the underlying mechanisms of PND and concern for risks associated with administering multiple cycles of cytotoxic chemotherapy in the inpatient setting, given her altered mental status and psychosis, contributed to the multidisciplinary decision to proceed with upfront surgical resection. We considered the potential for worsening of her PND with cytotoxic chemotherapy that could lead to rapid release of onconeuronal antigens and foreign epitopes resulting from a high volume of tumor cell death and breakdown. Surgical resection of the bulk of the tumor was considered as a potential rapid removal of the bulk of tumor cells, contributing to the formation of further autoimmune neuron-specific autoantibodies. It remains uncertain whether our patient may have responded differently to a more standard-of-care approach to breast cancer with neoadjuvant TCHP followed by surgical resection and radiation.
Our patient had residual disease in her axilla after the completion of 6 cycles of TCHP, requiring repeat surgical resection. Given the persistent disease in the absence of metastatic recurrence, we transitioned adjuvant therapy from HP to ado-trastuzumab emtansine in the spirit of the KATHERINE trial [3]. The KATHERINE trial evaluated patients with HER2-positive T1–T4 and N0–N3 breast cancer who had residual disease at the time of resection following treatment with neoadjuvant HER2-targeted therapy and chemotherapy. In this trial, 12 months of adjuvant ado-trastuzumab resulted in improved invasive disease-free survival compared to treatment with trastuzumab alone (hazard ratio, 0.50; 95% confidence interval, 0.39–0.64; p < 0.001). Although our patient received TCHP in the adjuvant setting, she was found to have residual nodal disease after 6 cycles of chemotherapy, and we felt that she would benefit from the changing maintenance adjuvant therapy to ado-trastuzumab emtansine.
This patient's case represents the first explicitly documented case of paraneoplastic LE in a patient with HER2-positive breast cancer due to an unclassified neural autoantibody. Although breast cancer is the most common cancer diagnosed in women, the presence of associated PNDs is less common than the presence of PNDs associated with other malignancies [6]. The HR-negative, HER2-positive breast cancer subtype is less common than other subtypes, and expression of anti-Yo antibodies in the serum or CSF has previously been reported in patients with associated PCD. Our patient had HR-negative HER2-positive breast cancer, yet did not carry anti-Yo antibodies nor did she have PCD, making her case quite unique. Her presentation and requirement for hospitalization meant that she was treated outside the standard of care, and highlights the need for understanding the pathophysiology of these PNDs; recognition of the need for further research into and delineation of atypical unclassified antibodies given the high incidence of patients without well-characterized antibodies; knowledge of the data regarding efficacy of treatment modalities such as immunosuppressive and anticancer therapies; and the need for tailoring treatment for a specific patient and their specific cancer.
ACKNOWLEDGMENTS
We thank Sharon Sams, MD, for her assistance in providing pathologic images.
Funding: This investigation was supported by the National Institutes of Health (NIH) under Ruth L. Kirschstein National Research Service Award T32CA236734-01. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Conflict of Interest: The authors declare that they have no competing interests.
Author Contributions:
Conceptualization: Shay RC, Diamond JR.
Resources: Shay RC.
Supervision: Diamond JR.
Visualization: Sams SB.
Writing - original draft: Shay RC.
Writing - review & editing: Shay RC, Diamond JR, Kagihara JA. | ADO-TRASTUZUMAB EMTANSINE, DIVALPROEX SODIUM, FOSPHENYTOIN, LACOSAMIDE, LEVETIRACETAM, PERTUZUMAB, PHENYTOIN, TRASTUZUMAB, ZOLPIDEM TARTRATE | DrugsGivenReaction | CC BY-NC | 33634625 | 19,418,864 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Seizure'. | Paraneoplastic Encephalitis Associated with Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.
Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.
INTRODUCTION
Paraneoplastic neurologic diseases (PND) including limbic encephalitis (LE) have been reported to occur in association with breast cancer for many decades, although its incidence is quite rare [1]. Breast cancer-related neurologic paraneoplastic syndromes can have diverse presentations, including sensory and motor-type neuropathies, paraneoplastic cerebellar degeneration (PCD), opsoclonus-myoclonus syndrome, stiff person syndrome, encephalomyelitis, and paraneoplastic retinopathy [1]. Because breast cancer-related paraneoplastic syndromes are uncommon, only limited data are available to support their association with specific breast cancer subsets, presence of certain histological subtypes, advanced clinical stage, or lymphovascular invasion [1].
The diagnosis of a paraneoplastic neurological disorder requires the presence of neurological symptoms, diagnosis of cancer within 4 years, exclusion of other neurological disorders, and at least one of the following findings: cerebrospinal fluid (CSF) analysis showing inflammation with negative cytology, brain magnetic resonance imaging (MRI) demonstrating characteristic hyperintensity signals on T2-weighted fluid attenuated inversion recovery images of the medial temporal lobe(s), or epileptic activity in the temporal lobes by electroencephalogram (EEG) [12]. The presence of autoantibodies in the blood or CSF is not necessary for diagnosis. Interestingly, neuron-specific autoantibodies are only found in approximately 60%–70% of patients with clinically diagnosed paraneoplastic syndromes associated with breast cancer [1]. Therefore, antibody testing may be helpful if positive, but the absence of antibodies cannot rule out paraneoplastic neurologic syndrome [1].
Herein, we report a unique case of a patient who presented with rapid-onset altered mental status and temporal lobe seizures along with no other obvious neurologic disorder based on extensive imaging as well as CSF and serum analyses in the setting of a new diagnosis of locally advanced hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
CASE REPORT
A 56-year-old woman was admitted to the hospital for psychosis, paranoia, hallucinations, and seizures. Two months before admission, she presented to her primary care physician with right upper extremity numbness and an MRI of the cervical spine that revealed degenerative disc disease. During the following weeks, she developed paranoia, psychosis, and hallucinations, leading to admission at a psychiatric facility. According to the evaluation and treatment of her psychiatric symptoms, the patient was transferred to a medical facility for further workup and to rule out organic causes.
Her past medical history included insomnia treated with zolpidem, but no prior psychiatric disorder. Surgical history was notable for left knee arthroscopy. Her family history included Alzheimer's dementia in her father and a brain tumor in her mother. The patient was living independently and was working before admission. She was a former smoker who did not consume alcohol, marijuana, or other drugs.
On initial presentation to the medical facility, EEG demonstrated focal subclinical seizures originating from the left temporal region. Continuous EEG confirmed frequent seizures, and she was started on multiple anti-epileptic drugs (AEDs), including fosphenytoin, phenytoin, lacosamide, divalproex, and levetiracetam. Her seizures were refractory to medical therapy, and the patient required intubation for airway protection. Brain MRI demonstrated no acute intracranial findings, including no findings specific for encephalitis but incidentally revealed a small right superior frontoparietal paramedian meningioma. Infectious workup, toxicology, blood counts, and electrolytes were all within normal limits, and we could not identify a cause for her seizures and changes in mental status. Computed tomography (CT) of the chest, abdomen, and pelvis revealed a 2.5-cm mass in the right breast with associated right axillary lymphadenopathy and no evidence of distant metastatic disease. Diagnostic lumbar puncture was performed and CSF analysis revealed a cell count of 4 white blood cells (WBC) (reference range, < 5 WBC), 324 red blood cells, glucose 59 mg/dL (reference range, < 300 mg/dL), protein 49 mg/dL (reference range, 18–58 mg/dL), oligoclonal bands, and elevated immunoglobulin G (IgG) index. A second CSF sample was obtained several days later and showed similar findings, and viral, bacterial, and fungal cultures were negative. Cytology was negative for malignant cells in both samples. A comprehensive serum paraneoplastic autoantibody panel and a CSF autoimmune epilepsy panel were both negative for autoantibodies (Table 1). However, the staining pattern was suggestive of the presence of an unknown neuron-specific autoantibody.
Table 1 Comprehensive paraneoplastic autoantibody and autoimmune epilepsy work-up
Serum paraneoplastic autoantibodies CSF autoimmune epilepsy labs
Test Result (reference value) Test Result (reference value)
ANNA-1 (Hu) Negative (< 1:240 titer) NMDA-R AB CBA Negative (negative)
ANNA-2 (Ri) Negative (< 1:240 titer) VGKC Complex AB IPA 0 (≤ 0.02 nmol/L)
ANNA-3 Negative (< 1:240 titer) LGI1-IgG CBA Negative (negative)
AGNA-1 Negative (< 1:240 titer) CASPR2-IgG CBA Negative (negative)
PCA-1 (Yo) Negative (< 1:240 titer) GAD65 AB Assay 0 (≤ 0.02 nmol/L)
PCA-2 Negative (< 1:240 titer) GABA-B-R AB CBA Negative (negative)
PCA-Tr Negative (< 1:240 titer) AMPA-R AB CBA Negative (negative)
Amphiphysin AB Negative (< 1:240 titer) ANNA-1 Negative (< 1:2 titer)
CRMP-5-IgG Negative (< 1:240 titer) ANNA-2 Negative (< 1:2 titer)
P/Q CAL CHAN AB 0.01 (≤ 0.02 nmol/L) ANNA-3 Negative (< 1:2 titer)
N-CAL CHAN AB 0 (≤ 0.03 nmol/L) AGNA-1 Negative (< 1:2 titer)
ACHR GANG NEUR AB 0 (≤ 0.02 nmol/L) PCA-2 Negative (< 1:2 titer)
NEUR K CHAN AB 0 (≤ 0.02 nmol/L) PCA-Tr Negative (< 1:2 titer)
STRIATIONAL AB Negative (< 1:240 titer) Amphiphysin AB Negative (< 1:2 titer)
CRMP-5-IgG Negative (< 1:2 titer)
CSF = cerebrospinal fluid; ANNA = anti-neuronal nuclear antibody; AGNA = anti-glial nuclear antibody; PCA = Purkinje cell cytoplasmic antibody; AB = antibody; CRMP-5 = collapsin response-mediator protein-5; IgG = immunoglobulin G; P/Q CAL CHAN = P/Q-type calcium channel; N-CAL CHAN = N-type calcium channel; ACHR GANG NEUR = acetylcholine receptor ganglionic neuronal; NEUR K = neuronal potassium channel; NMDA-R = N-methyl-d-aspartate receptor; CBA = collagen-binding activity; VGKC Complex AB IPA = neuronal voltage-gated potassium channel antibody; LGI1 = leucine-rich gliomainactivated 1; CASPR2 = contactin-associated protein-like 2; GAD65= glutamic acid decarboxylase; GABA-B-R = gamma aminobutyric acid receptor type B; AMPA-R = AMPA receptor.
The patient underwent biopsy of the right breast mass, which revealed invasive ductal carcinoma, grade 3, Ki-67 90%, estrogen receptor and progesterone receptor negative by immunohistochemical staining (IHC), HER2 equivocal with focal 2+ positivity by IHC, and positive with a HER2/CEN17 signal ratio of 3.2 by fluorescent in situ hybridization. The patient was diagnosed with American Joint Committee on Cancer anatomic stage IIB (cT2N1M0) HR-negative, HER2-positive breast cancer.
Given that paraneoplastic encephalitis is concerning in the setting of a new cancer diagnosis, she received empiric steroids and intravenous immunoglobulin (IVIG) with improvement in her seizures, allowing extubation. Her AEDs were weaned to lacosamide 200 mg twice daily and levetiracetam 1,500 mg twice daily, and she was later discharged from the hospital with neurology and oncology follow-up to receive breast cancer treatment.
Unfortunately, the patient experienced increased seizures shortly after hospital discharge and was admitted to the neurology service at our tertiary referral center with presumed paraneoplastic encephalitis. Plasma-exchange was initiated, and oncology was consulted for assistance in inpatient management. Physical examination revealed that the woman had anxiety and appeared her stated age of 56; a firm, non-tender, 3-cm mobile mass was palpated in her superior right breast with no overlying skin changes; a 3-cm firm right axillary lymph node was palpated. Neurologically, the patient was oriented appropriately and did not have any focal sensory or motor deficits. She had impaired short-term memory, word-finding difficulty, intermittent non-sensical speech, and paranoia. Repeat brain MRI demonstrated edema and abnormal enhancement involving the left mesial temporal lobe, predominantly in the amygdala (Figure 1). This finding was suggestive of paraneoplastic LE in the clinical context. A CT scan of the chest, abdomen, and pelvis again demonstrated a known right breast cancer with regional axillary lymphadenopathy without evidence of distant metastatic disease (Figure 2). Given these findings, she was diagnosed with LE, a PND, most likely related to her newly diagnosed stage IIB HR-negative HER2-positive breast cancer.
Figure 1 Brain magnetic resonance imaging with and without a contrast agent upon admission to our tertiary care facility. The image demonstrates edema and abnormal enhancement involving the left mesial temporal lobe, predominantly the amygdala, suggestive of paraneoplastic encephalitis given the clinical context.
Figure 2 CT of the chest, abdomen, and pelvis. (A) Chest CT image showing right axillary lymphadenopathy and (B) tumor in the lateral right breast with central calcification.
CT = computed tomography.
Although non-metastatic breast cancer is almost always treated in the outpatient setting, the patient required inpatient treatment because her breast cancer was felt to be the most likely underlying cause of her LE, and her ongoing psychosis and seizures made discharge unsafe. Following discussion in our multidisciplinary breast cancer tumor board, the patient received one dose of trastuzumab and pertuzumab (HP) followed by right mastectomy and axillary lymph node dissection. The final pathology revealed a 2.7-cm invasive micropapillary carcinoma, grade 3, HR-negative HER2-positive (3+ by IHC) in the right breast, and 6 of 7 positive axillary lymph nodes correlated with pathologic AJCC anatomic Stage IIIA (pT2N2M0) (Figure 3). Neuroendocrine markers were not assessed on the pathological specimen, and the specimens were not assessed specifically for the presence of tumor-infiltrating cells. Within a week of her surgery, she experienced enough improvement in her encephalitis, allowing discharge to a memory care facility under 24-hour supervision. She was able to receive adjuvant chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) for 6 cycles. During this time, she experienced no deterioration of neurological symptoms but rather had consistent improvement in her mental status. By the end of the 6 cycles of TCHP, her quality of life improved and she no longer required 24-hour supervision. Interestingly, her long-term memory remained relatively intact despite continued difficulty with short-term memory, including remembering day-to-day events and tasks.
Figure 3 Tissue obtained during initial lymph node dissection. (A) Invasive ductal carcinoma at 40× magnification on hematoxylin and eosin staining, and (B) invasive ductal carcinoma with human epidermal growth factor receptor 2-staining (brown) at 40× magnification.
Upon completion of adjuvant chemotherapy, she was referred for radiation oncology considering post-mastectomy chest wall radiation provided to multiple positive lymph nodes. Unfortunately, on CT, she was found to have an enlarged, abnormal axillary lymph node, which, when biopsied, showed metastatic breast cancer that was morphologically consistent with her primary tumor (Figure 4). PET/CT was performed for re-staging and demonstrated right axillary adenopathy, but there was no other evidence of metastatic disease (Figure 5). As a result, she underwent repeat axillary lymph node dissection with 3 of 3 positive lymph nodes with extracapsular extension. This was followed by adjuvant radiation to the chest wall and regional lymph nodes. Given her persistent disease after TCHP, the patient was transitioned to adjuvant ado-trastuzumab emtansine in accordance with the KATHERINE trial [3]. Over the course of this treatment, her mental status slowly improved, brain MRIs normalized (Figure 6), and she remained seizure-free. She currently continues to experience deficits in her short-term memory; however, she is able to manage her day-to-day tasks independently.
Figure 4 Radiation simulation computed tomography scan. Persistent right axillary lymphadenopathy is indicated with an arrow.
Figure 5 Re-staging positron emission tomography-computed tomography. The image shows a rounded right axillary lymph node (9 mm × 8 mm) demonstrating no abnormal uptake and slightly increased size before the examination (7 mm × 6 mm).
Figure 6 Change in brain MRI findings over time. (A, B) Outpatient follow-up brain MRIs at 5 months from treatment initiation. Since prior, significant improvement in T2 fluid attenuated inversion recovery medial temporal signal abnormality with decreased edema. Minimal signal abnormality involves the bilateral amygdalae. MRI findings suggest improved limbic encephalitis compared to that in two previous MRI studies. (C) Resolved abnormal signal involving the mesial temporal lobes, 9 months from the initiation of treatment.
MRI = magnetic resonance imaging.
DISCUSSION
This patient met all four criteria for the diagnosis of a paraneoplastic neurological disorder, with her mental status changes associated with temporal lobe seizures, a new diagnosis of breast cancer, exclusion of other neurologic disorders with extensive imaging and serum and CSF analyses, and temporal lobe changes on MRI. Her presentation was consistent with LE, and her response to breast cancer treatment also strongly suggests a PND related to newly diagnosed, locally advanced HR-negative, HER2-positive breast cancer.
PNDs are likely initiated as an immune response directed against autoantigens expressed in tumors. Initially, immune cell priming occurs in the tumor microenvironment, as tumor-associated neoepitopes are recognized as foreign by the immune system [1]. The increased cellular proliferation and necrosis that occur in the tumor microenvironment facilitate the expression previously “hidden” neoantigens. Proteinaceous cellular debris may be scavenged by dendritic cells and carried to lymph nodes and lymphoid organs, leading to the amplification of the anti-tumor immune response in B and T cells [1]. In the setting of PND, these exposed tumor-associated neoantigens may be structurally similar to neuronal proteins, leading to an antiauto-neuroantigen response, culminating in autoimmune or paraneoplastic syndromes [1]. In this clinical situation, antineuronal antibodies can often be found in both the serum and the CSF in patients with PND. Additionally, target paraneoplastic antigens are often expressed in both the implicated tumor and the affected parts of the nervous system [1].
Several histological and laboratory findings suggest and support immune-mediated pathology for PND. Autopsy and biopsy specimens obtained from the nervous system in patients with PND typically show neuronal loss in the affected areas associated with infiltration by B cells and CD4+ T-helper cells in the perivascular spaces and infiltration of cytotoxic CD8+ T cells in the interstitial spaces [1]. CSF examination often demonstrates increased nucleated cells, oligoclonal bands, and intrathecal IgG synthesis, consistent with an inflammatory or immune-mediated process [1]. Furthering our understanding of the pathogenesis of PND has been the advent and widespread use of immune checkpoint blockade. One would hypothesize that this class of medication is very active against tumors underlying PND, which are often densely infiltrated with tumor-infiltrating lymphocytes, but they have unfortunately been repeatedly reported to worsen or even initially reveal PND. In support of an immune-mediated process, tumors associated with PND are often small [1]. In some instances, a tumor may not exist at all in the case of spontaneous remissions at the time of neurological presentations, suggesting that some PND without a detectable tumor may actually result from an immune-mediated elimination of the primary tumor [1]. In such circumstances, one could argue that CNS dysfunction actually reflects an effective immune response to systemic cancer [1].
The pathogenic role of paraneoplastic antibodies has been proven for those that are directed against easily accessible antigens located at the cell surface, allowing antineuronal antibodies to interfere with neuronal signaling or synaptic transmission. However, it is more difficult to explain the pathogenic role of antibodies directed against intracellularly located paraneoplastic antigens such as the Yo antigen in the cytoplasm, or the Hu and Ri antigens found in the nucleus. In these instances, the cellular immune response to these antigens through cytotoxic T cells is likely responsible for the neurological damage [1]. Experimental models and analyses of autopsied and biopsied tissues suggest that CD8+ cytotoxic T cells are at the core of PNDs for which the antigens of pathogenic antibodies are within the cell [1]. While intracellular antigens are not readily accessible to an immune incursion, peptides from intracellular proteins are displayed on major histocompatibility complex class I molecules, which are then available to peptide-specific cytotoxic T cells [1]. It stands to reason then that antibodies targeting intracellular antigens, which can be found in the serum and CSF, are not pathogenic, but rather are markers of a T cell-effected neuronal damage process [1].
The most common anti-neuronal antibodies in paraneoplastic LE are anti-Hu (ANNA-1), followed by anti-Ta (PNMA2) and anti-Ma (PNMA1/2) [4]. The most common anti-neuronal autoantibodies seen in patients with breast cancers are anti-Yo (Purkinje cell cytoplasmic antibody type 1), amphiphysin-IgG, and anti-Ri (ANNA-2) [2]. PND associated with HER2-positive breast cancers, which account for approximately 15% of all breast cancer diagnoses, have almost exclusively been reported to have anti-Yo antibodies [5]. Rojas-Marcos et al. [5] published a retrospective review of 27 patients with breast cancer and anti-Yo antibodies, assessing HER2-positivity, which was found in 26 (96.3%) of them, whereas only 2 of 19 (10.5%) patients with anti-Ri-associated PND were found to be HER2-positive. A thorough review of the literature reveals several case reports reporting PNDs in HER2-positive breast cancer, the majority of which are locally advanced, have anti-Yo antibodies, and are classified as PCD (Table 2). We were unable to find any prior reports of HER2-positive breast cancer with associated LE. In reviewing Murphy et al's [2] series of 56 breast cancer patients with PND, the majority of patients had stage II disease (26 patients, 46.4%), but no patients had HR-negative, HER2-positive breast cancer, and only 1 patient had a previously undefined anti-neuronal antibody, which resulted in cerebellar ataxia and peripheral neuropathy. To the best of our knowledge, our patient represents the first documented case of a HER2-positive breast cancer underlying paraneoplastic LE. It also represents a unique case in the presence of an anti-neural antibody associated with this breast cancer subtype that is rare enough that it has not been further classified or accepted into the standard paraneoplastic neurological autoimmune workup.
Table 2 Case reports detailing HER2-positive breast cancer PNDs
Reference HR/HER2 status Histology Stage Antineuronal antibody present PND syndrome
Olmez et al. [6] HR+/HER2+ IDC IIA Anti-Ri Opsoclonus
Myoclonus
Le May et al. [7] HR−/HER2+ IDC IIB Anti-Yo PCD
Dalmau et al. [8] HR−/HER2+ IDC IIA Anti-Yo PCD
Diamanti et al. [9] HR+/HER2+ IDC IIIC None LMND
Ogita et al. [10] HR−/HER2+ IDC IIIC Anti-Yo PCD
Dorn et al. [11] HR−/HER2+ IDC IIIA Anti-Yo PCD
Rupasinghe and Butler [12] Unknown HR/HER2+ Poorly differentiated adenocarcinoma IIA Anti-Yo PCD
Frings et al. [13] HR−/HER2+ ILC IIIB Anti-Yo PCD
Sancho et al. [14] HR+/HER2+ IDC IIB Anti-Yo PCD
HER2 = human epidermal growth factor receptor 2; PND = paraneoplastic neurologic disorder; HR = hormone receptor; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; PCD = paraneoplastic cerebellar degeneration; LMND = lower motor neuron disease.
The most effective therapy for cancer-related PND is the treatment of the underlying malignancy. Gultekin et al. [4] reported 50 patients with PND, including four with breast cancer, showing that treatment of the tumor was more effective in improving neurological outcomes than the use of immunosuppression. Improvement was observed in 38% of anti-Hu patients, 30% of anti-Ta patients, and 64% of patients without these antibodies [4]. In a separate case series, Candler et al. [15] reported that 14% of patients (9/64) with PND had an associated breast cancer (of unknown subtype) and that the only treatment that led to improvement or stabilization of neurologic function was cancer treatment. Aside from cancer therapy, numerous treatment modalities have been investigated in PND and have been found to have limited efficacy. Despite this, immunosuppressive therapy is often used as a bridge to more definitive anticancer therapy. This is especially the case in patients diagnosed with PND as the first symptom of malignancy and before a formal diagnosis. Unfortunately, most patients with PND do not achieve full recovery even with anticancer therapy, and treatment of the underlying malignancy in PND can often stabilize only neurological symptoms, rather than lead to consistent long-term improvements. Finally, the prognosis of PND remains poor, and generally, any level of stabilization or improvement in neurologic symptoms that occurs within the first few months of diagnosis, and treatment becomes a new baseline for these patients.
While our patient initially had slight transient improvements with immunosuppression in the form of IVIG, steroids, and plasma exchange, real improvement was not seen until she underwent surgical resection and began receiving systemic therapy. The decision to proceed with surgical resection upfront as compared to initiating neoadjuvant chemotherapy with TCHP immediately was challenging. Our usual standard of care would be to proceed with neoadjuvant chemotherapy in the setting of node-positive, HER2-positive breast cancer. This approach can often lead to breast-conserving surgery and may even downstage the axilla, allowing for sentinel lymph node biopsy rather than axillary lymph node dissection in select patients. The use of neoadjuvant chemotherapy also allows the use of pathologic complete response as a prognostic marker that strongly correlated with improved disease-free and overall survival and tailoring adjuvant HER2-directed therapy based on response.
In our patient, however, the underlying mechanisms of PND and concern for risks associated with administering multiple cycles of cytotoxic chemotherapy in the inpatient setting, given her altered mental status and psychosis, contributed to the multidisciplinary decision to proceed with upfront surgical resection. We considered the potential for worsening of her PND with cytotoxic chemotherapy that could lead to rapid release of onconeuronal antigens and foreign epitopes resulting from a high volume of tumor cell death and breakdown. Surgical resection of the bulk of the tumor was considered as a potential rapid removal of the bulk of tumor cells, contributing to the formation of further autoimmune neuron-specific autoantibodies. It remains uncertain whether our patient may have responded differently to a more standard-of-care approach to breast cancer with neoadjuvant TCHP followed by surgical resection and radiation.
Our patient had residual disease in her axilla after the completion of 6 cycles of TCHP, requiring repeat surgical resection. Given the persistent disease in the absence of metastatic recurrence, we transitioned adjuvant therapy from HP to ado-trastuzumab emtansine in the spirit of the KATHERINE trial [3]. The KATHERINE trial evaluated patients with HER2-positive T1–T4 and N0–N3 breast cancer who had residual disease at the time of resection following treatment with neoadjuvant HER2-targeted therapy and chemotherapy. In this trial, 12 months of adjuvant ado-trastuzumab resulted in improved invasive disease-free survival compared to treatment with trastuzumab alone (hazard ratio, 0.50; 95% confidence interval, 0.39–0.64; p < 0.001). Although our patient received TCHP in the adjuvant setting, she was found to have residual nodal disease after 6 cycles of chemotherapy, and we felt that she would benefit from the changing maintenance adjuvant therapy to ado-trastuzumab emtansine.
This patient's case represents the first explicitly documented case of paraneoplastic LE in a patient with HER2-positive breast cancer due to an unclassified neural autoantibody. Although breast cancer is the most common cancer diagnosed in women, the presence of associated PNDs is less common than the presence of PNDs associated with other malignancies [6]. The HR-negative, HER2-positive breast cancer subtype is less common than other subtypes, and expression of anti-Yo antibodies in the serum or CSF has previously been reported in patients with associated PCD. Our patient had HR-negative HER2-positive breast cancer, yet did not carry anti-Yo antibodies nor did she have PCD, making her case quite unique. Her presentation and requirement for hospitalization meant that she was treated outside the standard of care, and highlights the need for understanding the pathophysiology of these PNDs; recognition of the need for further research into and delineation of atypical unclassified antibodies given the high incidence of patients without well-characterized antibodies; knowledge of the data regarding efficacy of treatment modalities such as immunosuppressive and anticancer therapies; and the need for tailoring treatment for a specific patient and their specific cancer.
ACKNOWLEDGMENTS
We thank Sharon Sams, MD, for her assistance in providing pathologic images.
Funding: This investigation was supported by the National Institutes of Health (NIH) under Ruth L. Kirschstein National Research Service Award T32CA236734-01. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Conflict of Interest: The authors declare that they have no competing interests.
Author Contributions:
Conceptualization: Shay RC, Diamond JR.
Resources: Shay RC.
Supervision: Diamond JR.
Visualization: Sams SB.
Writing - original draft: Shay RC.
Writing - review & editing: Shay RC, Diamond JR, Kagihara JA. | ADO-TRASTUZUMAB EMTANSINE, DIVALPROEX SODIUM, FOSPHENYTOIN, LACOSAMIDE, LEVETIRACETAM, PERTUZUMAB, PHENYTOIN, TRASTUZUMAB, ZOLPIDEM TARTRATE | DrugsGivenReaction | CC BY-NC | 33634625 | 19,418,864 | 2021-02 |
What was the outcome of reaction 'Seizure'? | Paraneoplastic Encephalitis Associated with Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.
Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.
INTRODUCTION
Paraneoplastic neurologic diseases (PND) including limbic encephalitis (LE) have been reported to occur in association with breast cancer for many decades, although its incidence is quite rare [1]. Breast cancer-related neurologic paraneoplastic syndromes can have diverse presentations, including sensory and motor-type neuropathies, paraneoplastic cerebellar degeneration (PCD), opsoclonus-myoclonus syndrome, stiff person syndrome, encephalomyelitis, and paraneoplastic retinopathy [1]. Because breast cancer-related paraneoplastic syndromes are uncommon, only limited data are available to support their association with specific breast cancer subsets, presence of certain histological subtypes, advanced clinical stage, or lymphovascular invasion [1].
The diagnosis of a paraneoplastic neurological disorder requires the presence of neurological symptoms, diagnosis of cancer within 4 years, exclusion of other neurological disorders, and at least one of the following findings: cerebrospinal fluid (CSF) analysis showing inflammation with negative cytology, brain magnetic resonance imaging (MRI) demonstrating characteristic hyperintensity signals on T2-weighted fluid attenuated inversion recovery images of the medial temporal lobe(s), or epileptic activity in the temporal lobes by electroencephalogram (EEG) [12]. The presence of autoantibodies in the blood or CSF is not necessary for diagnosis. Interestingly, neuron-specific autoantibodies are only found in approximately 60%–70% of patients with clinically diagnosed paraneoplastic syndromes associated with breast cancer [1]. Therefore, antibody testing may be helpful if positive, but the absence of antibodies cannot rule out paraneoplastic neurologic syndrome [1].
Herein, we report a unique case of a patient who presented with rapid-onset altered mental status and temporal lobe seizures along with no other obvious neurologic disorder based on extensive imaging as well as CSF and serum analyses in the setting of a new diagnosis of locally advanced hormone receptor (HR)-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
CASE REPORT
A 56-year-old woman was admitted to the hospital for psychosis, paranoia, hallucinations, and seizures. Two months before admission, she presented to her primary care physician with right upper extremity numbness and an MRI of the cervical spine that revealed degenerative disc disease. During the following weeks, she developed paranoia, psychosis, and hallucinations, leading to admission at a psychiatric facility. According to the evaluation and treatment of her psychiatric symptoms, the patient was transferred to a medical facility for further workup and to rule out organic causes.
Her past medical history included insomnia treated with zolpidem, but no prior psychiatric disorder. Surgical history was notable for left knee arthroscopy. Her family history included Alzheimer's dementia in her father and a brain tumor in her mother. The patient was living independently and was working before admission. She was a former smoker who did not consume alcohol, marijuana, or other drugs.
On initial presentation to the medical facility, EEG demonstrated focal subclinical seizures originating from the left temporal region. Continuous EEG confirmed frequent seizures, and she was started on multiple anti-epileptic drugs (AEDs), including fosphenytoin, phenytoin, lacosamide, divalproex, and levetiracetam. Her seizures were refractory to medical therapy, and the patient required intubation for airway protection. Brain MRI demonstrated no acute intracranial findings, including no findings specific for encephalitis but incidentally revealed a small right superior frontoparietal paramedian meningioma. Infectious workup, toxicology, blood counts, and electrolytes were all within normal limits, and we could not identify a cause for her seizures and changes in mental status. Computed tomography (CT) of the chest, abdomen, and pelvis revealed a 2.5-cm mass in the right breast with associated right axillary lymphadenopathy and no evidence of distant metastatic disease. Diagnostic lumbar puncture was performed and CSF analysis revealed a cell count of 4 white blood cells (WBC) (reference range, < 5 WBC), 324 red blood cells, glucose 59 mg/dL (reference range, < 300 mg/dL), protein 49 mg/dL (reference range, 18–58 mg/dL), oligoclonal bands, and elevated immunoglobulin G (IgG) index. A second CSF sample was obtained several days later and showed similar findings, and viral, bacterial, and fungal cultures were negative. Cytology was negative for malignant cells in both samples. A comprehensive serum paraneoplastic autoantibody panel and a CSF autoimmune epilepsy panel were both negative for autoantibodies (Table 1). However, the staining pattern was suggestive of the presence of an unknown neuron-specific autoantibody.
Table 1 Comprehensive paraneoplastic autoantibody and autoimmune epilepsy work-up
Serum paraneoplastic autoantibodies CSF autoimmune epilepsy labs
Test Result (reference value) Test Result (reference value)
ANNA-1 (Hu) Negative (< 1:240 titer) NMDA-R AB CBA Negative (negative)
ANNA-2 (Ri) Negative (< 1:240 titer) VGKC Complex AB IPA 0 (≤ 0.02 nmol/L)
ANNA-3 Negative (< 1:240 titer) LGI1-IgG CBA Negative (negative)
AGNA-1 Negative (< 1:240 titer) CASPR2-IgG CBA Negative (negative)
PCA-1 (Yo) Negative (< 1:240 titer) GAD65 AB Assay 0 (≤ 0.02 nmol/L)
PCA-2 Negative (< 1:240 titer) GABA-B-R AB CBA Negative (negative)
PCA-Tr Negative (< 1:240 titer) AMPA-R AB CBA Negative (negative)
Amphiphysin AB Negative (< 1:240 titer) ANNA-1 Negative (< 1:2 titer)
CRMP-5-IgG Negative (< 1:240 titer) ANNA-2 Negative (< 1:2 titer)
P/Q CAL CHAN AB 0.01 (≤ 0.02 nmol/L) ANNA-3 Negative (< 1:2 titer)
N-CAL CHAN AB 0 (≤ 0.03 nmol/L) AGNA-1 Negative (< 1:2 titer)
ACHR GANG NEUR AB 0 (≤ 0.02 nmol/L) PCA-2 Negative (< 1:2 titer)
NEUR K CHAN AB 0 (≤ 0.02 nmol/L) PCA-Tr Negative (< 1:2 titer)
STRIATIONAL AB Negative (< 1:240 titer) Amphiphysin AB Negative (< 1:2 titer)
CRMP-5-IgG Negative (< 1:2 titer)
CSF = cerebrospinal fluid; ANNA = anti-neuronal nuclear antibody; AGNA = anti-glial nuclear antibody; PCA = Purkinje cell cytoplasmic antibody; AB = antibody; CRMP-5 = collapsin response-mediator protein-5; IgG = immunoglobulin G; P/Q CAL CHAN = P/Q-type calcium channel; N-CAL CHAN = N-type calcium channel; ACHR GANG NEUR = acetylcholine receptor ganglionic neuronal; NEUR K = neuronal potassium channel; NMDA-R = N-methyl-d-aspartate receptor; CBA = collagen-binding activity; VGKC Complex AB IPA = neuronal voltage-gated potassium channel antibody; LGI1 = leucine-rich gliomainactivated 1; CASPR2 = contactin-associated protein-like 2; GAD65= glutamic acid decarboxylase; GABA-B-R = gamma aminobutyric acid receptor type B; AMPA-R = AMPA receptor.
The patient underwent biopsy of the right breast mass, which revealed invasive ductal carcinoma, grade 3, Ki-67 90%, estrogen receptor and progesterone receptor negative by immunohistochemical staining (IHC), HER2 equivocal with focal 2+ positivity by IHC, and positive with a HER2/CEN17 signal ratio of 3.2 by fluorescent in situ hybridization. The patient was diagnosed with American Joint Committee on Cancer anatomic stage IIB (cT2N1M0) HR-negative, HER2-positive breast cancer.
Given that paraneoplastic encephalitis is concerning in the setting of a new cancer diagnosis, she received empiric steroids and intravenous immunoglobulin (IVIG) with improvement in her seizures, allowing extubation. Her AEDs were weaned to lacosamide 200 mg twice daily and levetiracetam 1,500 mg twice daily, and she was later discharged from the hospital with neurology and oncology follow-up to receive breast cancer treatment.
Unfortunately, the patient experienced increased seizures shortly after hospital discharge and was admitted to the neurology service at our tertiary referral center with presumed paraneoplastic encephalitis. Plasma-exchange was initiated, and oncology was consulted for assistance in inpatient management. Physical examination revealed that the woman had anxiety and appeared her stated age of 56; a firm, non-tender, 3-cm mobile mass was palpated in her superior right breast with no overlying skin changes; a 3-cm firm right axillary lymph node was palpated. Neurologically, the patient was oriented appropriately and did not have any focal sensory or motor deficits. She had impaired short-term memory, word-finding difficulty, intermittent non-sensical speech, and paranoia. Repeat brain MRI demonstrated edema and abnormal enhancement involving the left mesial temporal lobe, predominantly in the amygdala (Figure 1). This finding was suggestive of paraneoplastic LE in the clinical context. A CT scan of the chest, abdomen, and pelvis again demonstrated a known right breast cancer with regional axillary lymphadenopathy without evidence of distant metastatic disease (Figure 2). Given these findings, she was diagnosed with LE, a PND, most likely related to her newly diagnosed stage IIB HR-negative HER2-positive breast cancer.
Figure 1 Brain magnetic resonance imaging with and without a contrast agent upon admission to our tertiary care facility. The image demonstrates edema and abnormal enhancement involving the left mesial temporal lobe, predominantly the amygdala, suggestive of paraneoplastic encephalitis given the clinical context.
Figure 2 CT of the chest, abdomen, and pelvis. (A) Chest CT image showing right axillary lymphadenopathy and (B) tumor in the lateral right breast with central calcification.
CT = computed tomography.
Although non-metastatic breast cancer is almost always treated in the outpatient setting, the patient required inpatient treatment because her breast cancer was felt to be the most likely underlying cause of her LE, and her ongoing psychosis and seizures made discharge unsafe. Following discussion in our multidisciplinary breast cancer tumor board, the patient received one dose of trastuzumab and pertuzumab (HP) followed by right mastectomy and axillary lymph node dissection. The final pathology revealed a 2.7-cm invasive micropapillary carcinoma, grade 3, HR-negative HER2-positive (3+ by IHC) in the right breast, and 6 of 7 positive axillary lymph nodes correlated with pathologic AJCC anatomic Stage IIIA (pT2N2M0) (Figure 3). Neuroendocrine markers were not assessed on the pathological specimen, and the specimens were not assessed specifically for the presence of tumor-infiltrating cells. Within a week of her surgery, she experienced enough improvement in her encephalitis, allowing discharge to a memory care facility under 24-hour supervision. She was able to receive adjuvant chemotherapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) for 6 cycles. During this time, she experienced no deterioration of neurological symptoms but rather had consistent improvement in her mental status. By the end of the 6 cycles of TCHP, her quality of life improved and she no longer required 24-hour supervision. Interestingly, her long-term memory remained relatively intact despite continued difficulty with short-term memory, including remembering day-to-day events and tasks.
Figure 3 Tissue obtained during initial lymph node dissection. (A) Invasive ductal carcinoma at 40× magnification on hematoxylin and eosin staining, and (B) invasive ductal carcinoma with human epidermal growth factor receptor 2-staining (brown) at 40× magnification.
Upon completion of adjuvant chemotherapy, she was referred for radiation oncology considering post-mastectomy chest wall radiation provided to multiple positive lymph nodes. Unfortunately, on CT, she was found to have an enlarged, abnormal axillary lymph node, which, when biopsied, showed metastatic breast cancer that was morphologically consistent with her primary tumor (Figure 4). PET/CT was performed for re-staging and demonstrated right axillary adenopathy, but there was no other evidence of metastatic disease (Figure 5). As a result, she underwent repeat axillary lymph node dissection with 3 of 3 positive lymph nodes with extracapsular extension. This was followed by adjuvant radiation to the chest wall and regional lymph nodes. Given her persistent disease after TCHP, the patient was transitioned to adjuvant ado-trastuzumab emtansine in accordance with the KATHERINE trial [3]. Over the course of this treatment, her mental status slowly improved, brain MRIs normalized (Figure 6), and she remained seizure-free. She currently continues to experience deficits in her short-term memory; however, she is able to manage her day-to-day tasks independently.
Figure 4 Radiation simulation computed tomography scan. Persistent right axillary lymphadenopathy is indicated with an arrow.
Figure 5 Re-staging positron emission tomography-computed tomography. The image shows a rounded right axillary lymph node (9 mm × 8 mm) demonstrating no abnormal uptake and slightly increased size before the examination (7 mm × 6 mm).
Figure 6 Change in brain MRI findings over time. (A, B) Outpatient follow-up brain MRIs at 5 months from treatment initiation. Since prior, significant improvement in T2 fluid attenuated inversion recovery medial temporal signal abnormality with decreased edema. Minimal signal abnormality involves the bilateral amygdalae. MRI findings suggest improved limbic encephalitis compared to that in two previous MRI studies. (C) Resolved abnormal signal involving the mesial temporal lobes, 9 months from the initiation of treatment.
MRI = magnetic resonance imaging.
DISCUSSION
This patient met all four criteria for the diagnosis of a paraneoplastic neurological disorder, with her mental status changes associated with temporal lobe seizures, a new diagnosis of breast cancer, exclusion of other neurologic disorders with extensive imaging and serum and CSF analyses, and temporal lobe changes on MRI. Her presentation was consistent with LE, and her response to breast cancer treatment also strongly suggests a PND related to newly diagnosed, locally advanced HR-negative, HER2-positive breast cancer.
PNDs are likely initiated as an immune response directed against autoantigens expressed in tumors. Initially, immune cell priming occurs in the tumor microenvironment, as tumor-associated neoepitopes are recognized as foreign by the immune system [1]. The increased cellular proliferation and necrosis that occur in the tumor microenvironment facilitate the expression previously “hidden” neoantigens. Proteinaceous cellular debris may be scavenged by dendritic cells and carried to lymph nodes and lymphoid organs, leading to the amplification of the anti-tumor immune response in B and T cells [1]. In the setting of PND, these exposed tumor-associated neoantigens may be structurally similar to neuronal proteins, leading to an antiauto-neuroantigen response, culminating in autoimmune or paraneoplastic syndromes [1]. In this clinical situation, antineuronal antibodies can often be found in both the serum and the CSF in patients with PND. Additionally, target paraneoplastic antigens are often expressed in both the implicated tumor and the affected parts of the nervous system [1].
Several histological and laboratory findings suggest and support immune-mediated pathology for PND. Autopsy and biopsy specimens obtained from the nervous system in patients with PND typically show neuronal loss in the affected areas associated with infiltration by B cells and CD4+ T-helper cells in the perivascular spaces and infiltration of cytotoxic CD8+ T cells in the interstitial spaces [1]. CSF examination often demonstrates increased nucleated cells, oligoclonal bands, and intrathecal IgG synthesis, consistent with an inflammatory or immune-mediated process [1]. Furthering our understanding of the pathogenesis of PND has been the advent and widespread use of immune checkpoint blockade. One would hypothesize that this class of medication is very active against tumors underlying PND, which are often densely infiltrated with tumor-infiltrating lymphocytes, but they have unfortunately been repeatedly reported to worsen or even initially reveal PND. In support of an immune-mediated process, tumors associated with PND are often small [1]. In some instances, a tumor may not exist at all in the case of spontaneous remissions at the time of neurological presentations, suggesting that some PND without a detectable tumor may actually result from an immune-mediated elimination of the primary tumor [1]. In such circumstances, one could argue that CNS dysfunction actually reflects an effective immune response to systemic cancer [1].
The pathogenic role of paraneoplastic antibodies has been proven for those that are directed against easily accessible antigens located at the cell surface, allowing antineuronal antibodies to interfere with neuronal signaling or synaptic transmission. However, it is more difficult to explain the pathogenic role of antibodies directed against intracellularly located paraneoplastic antigens such as the Yo antigen in the cytoplasm, or the Hu and Ri antigens found in the nucleus. In these instances, the cellular immune response to these antigens through cytotoxic T cells is likely responsible for the neurological damage [1]. Experimental models and analyses of autopsied and biopsied tissues suggest that CD8+ cytotoxic T cells are at the core of PNDs for which the antigens of pathogenic antibodies are within the cell [1]. While intracellular antigens are not readily accessible to an immune incursion, peptides from intracellular proteins are displayed on major histocompatibility complex class I molecules, which are then available to peptide-specific cytotoxic T cells [1]. It stands to reason then that antibodies targeting intracellular antigens, which can be found in the serum and CSF, are not pathogenic, but rather are markers of a T cell-effected neuronal damage process [1].
The most common anti-neuronal antibodies in paraneoplastic LE are anti-Hu (ANNA-1), followed by anti-Ta (PNMA2) and anti-Ma (PNMA1/2) [4]. The most common anti-neuronal autoantibodies seen in patients with breast cancers are anti-Yo (Purkinje cell cytoplasmic antibody type 1), amphiphysin-IgG, and anti-Ri (ANNA-2) [2]. PND associated with HER2-positive breast cancers, which account for approximately 15% of all breast cancer diagnoses, have almost exclusively been reported to have anti-Yo antibodies [5]. Rojas-Marcos et al. [5] published a retrospective review of 27 patients with breast cancer and anti-Yo antibodies, assessing HER2-positivity, which was found in 26 (96.3%) of them, whereas only 2 of 19 (10.5%) patients with anti-Ri-associated PND were found to be HER2-positive. A thorough review of the literature reveals several case reports reporting PNDs in HER2-positive breast cancer, the majority of which are locally advanced, have anti-Yo antibodies, and are classified as PCD (Table 2). We were unable to find any prior reports of HER2-positive breast cancer with associated LE. In reviewing Murphy et al's [2] series of 56 breast cancer patients with PND, the majority of patients had stage II disease (26 patients, 46.4%), but no patients had HR-negative, HER2-positive breast cancer, and only 1 patient had a previously undefined anti-neuronal antibody, which resulted in cerebellar ataxia and peripheral neuropathy. To the best of our knowledge, our patient represents the first documented case of a HER2-positive breast cancer underlying paraneoplastic LE. It also represents a unique case in the presence of an anti-neural antibody associated with this breast cancer subtype that is rare enough that it has not been further classified or accepted into the standard paraneoplastic neurological autoimmune workup.
Table 2 Case reports detailing HER2-positive breast cancer PNDs
Reference HR/HER2 status Histology Stage Antineuronal antibody present PND syndrome
Olmez et al. [6] HR+/HER2+ IDC IIA Anti-Ri Opsoclonus
Myoclonus
Le May et al. [7] HR−/HER2+ IDC IIB Anti-Yo PCD
Dalmau et al. [8] HR−/HER2+ IDC IIA Anti-Yo PCD
Diamanti et al. [9] HR+/HER2+ IDC IIIC None LMND
Ogita et al. [10] HR−/HER2+ IDC IIIC Anti-Yo PCD
Dorn et al. [11] HR−/HER2+ IDC IIIA Anti-Yo PCD
Rupasinghe and Butler [12] Unknown HR/HER2+ Poorly differentiated adenocarcinoma IIA Anti-Yo PCD
Frings et al. [13] HR−/HER2+ ILC IIIB Anti-Yo PCD
Sancho et al. [14] HR+/HER2+ IDC IIB Anti-Yo PCD
HER2 = human epidermal growth factor receptor 2; PND = paraneoplastic neurologic disorder; HR = hormone receptor; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; PCD = paraneoplastic cerebellar degeneration; LMND = lower motor neuron disease.
The most effective therapy for cancer-related PND is the treatment of the underlying malignancy. Gultekin et al. [4] reported 50 patients with PND, including four with breast cancer, showing that treatment of the tumor was more effective in improving neurological outcomes than the use of immunosuppression. Improvement was observed in 38% of anti-Hu patients, 30% of anti-Ta patients, and 64% of patients without these antibodies [4]. In a separate case series, Candler et al. [15] reported that 14% of patients (9/64) with PND had an associated breast cancer (of unknown subtype) and that the only treatment that led to improvement or stabilization of neurologic function was cancer treatment. Aside from cancer therapy, numerous treatment modalities have been investigated in PND and have been found to have limited efficacy. Despite this, immunosuppressive therapy is often used as a bridge to more definitive anticancer therapy. This is especially the case in patients diagnosed with PND as the first symptom of malignancy and before a formal diagnosis. Unfortunately, most patients with PND do not achieve full recovery even with anticancer therapy, and treatment of the underlying malignancy in PND can often stabilize only neurological symptoms, rather than lead to consistent long-term improvements. Finally, the prognosis of PND remains poor, and generally, any level of stabilization or improvement in neurologic symptoms that occurs within the first few months of diagnosis, and treatment becomes a new baseline for these patients.
While our patient initially had slight transient improvements with immunosuppression in the form of IVIG, steroids, and plasma exchange, real improvement was not seen until she underwent surgical resection and began receiving systemic therapy. The decision to proceed with surgical resection upfront as compared to initiating neoadjuvant chemotherapy with TCHP immediately was challenging. Our usual standard of care would be to proceed with neoadjuvant chemotherapy in the setting of node-positive, HER2-positive breast cancer. This approach can often lead to breast-conserving surgery and may even downstage the axilla, allowing for sentinel lymph node biopsy rather than axillary lymph node dissection in select patients. The use of neoadjuvant chemotherapy also allows the use of pathologic complete response as a prognostic marker that strongly correlated with improved disease-free and overall survival and tailoring adjuvant HER2-directed therapy based on response.
In our patient, however, the underlying mechanisms of PND and concern for risks associated with administering multiple cycles of cytotoxic chemotherapy in the inpatient setting, given her altered mental status and psychosis, contributed to the multidisciplinary decision to proceed with upfront surgical resection. We considered the potential for worsening of her PND with cytotoxic chemotherapy that could lead to rapid release of onconeuronal antigens and foreign epitopes resulting from a high volume of tumor cell death and breakdown. Surgical resection of the bulk of the tumor was considered as a potential rapid removal of the bulk of tumor cells, contributing to the formation of further autoimmune neuron-specific autoantibodies. It remains uncertain whether our patient may have responded differently to a more standard-of-care approach to breast cancer with neoadjuvant TCHP followed by surgical resection and radiation.
Our patient had residual disease in her axilla after the completion of 6 cycles of TCHP, requiring repeat surgical resection. Given the persistent disease in the absence of metastatic recurrence, we transitioned adjuvant therapy from HP to ado-trastuzumab emtansine in the spirit of the KATHERINE trial [3]. The KATHERINE trial evaluated patients with HER2-positive T1–T4 and N0–N3 breast cancer who had residual disease at the time of resection following treatment with neoadjuvant HER2-targeted therapy and chemotherapy. In this trial, 12 months of adjuvant ado-trastuzumab resulted in improved invasive disease-free survival compared to treatment with trastuzumab alone (hazard ratio, 0.50; 95% confidence interval, 0.39–0.64; p < 0.001). Although our patient received TCHP in the adjuvant setting, she was found to have residual nodal disease after 6 cycles of chemotherapy, and we felt that she would benefit from the changing maintenance adjuvant therapy to ado-trastuzumab emtansine.
This patient's case represents the first explicitly documented case of paraneoplastic LE in a patient with HER2-positive breast cancer due to an unclassified neural autoantibody. Although breast cancer is the most common cancer diagnosed in women, the presence of associated PNDs is less common than the presence of PNDs associated with other malignancies [6]. The HR-negative, HER2-positive breast cancer subtype is less common than other subtypes, and expression of anti-Yo antibodies in the serum or CSF has previously been reported in patients with associated PCD. Our patient had HR-negative HER2-positive breast cancer, yet did not carry anti-Yo antibodies nor did she have PCD, making her case quite unique. Her presentation and requirement for hospitalization meant that she was treated outside the standard of care, and highlights the need for understanding the pathophysiology of these PNDs; recognition of the need for further research into and delineation of atypical unclassified antibodies given the high incidence of patients without well-characterized antibodies; knowledge of the data regarding efficacy of treatment modalities such as immunosuppressive and anticancer therapies; and the need for tailoring treatment for a specific patient and their specific cancer.
ACKNOWLEDGMENTS
We thank Sharon Sams, MD, for her assistance in providing pathologic images.
Funding: This investigation was supported by the National Institutes of Health (NIH) under Ruth L. Kirschstein National Research Service Award T32CA236734-01. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Conflict of Interest: The authors declare that they have no competing interests.
Author Contributions:
Conceptualization: Shay RC, Diamond JR.
Resources: Shay RC.
Supervision: Diamond JR.
Visualization: Sams SB.
Writing - original draft: Shay RC.
Writing - review & editing: Shay RC, Diamond JR, Kagihara JA. | Recovered | ReactionOutcome | CC BY-NC | 33634625 | 19,418,864 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperferritinaemia'. | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | MYCOPHENOLIC ACID, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33635018 | 18,985,815 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | MYCOPHENOLIC ACID, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33635018 | 18,985,815 | 2021-03 |
What was the dosage of drug 'BASILIXIMAB'? | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | UNKNOWN | DrugDosageText | CC BY-NC | 33635018 | 19,289,501 | 2021-03 |
What was the dosage of drug 'UNSPECIFIED INGREDIENT'? | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | UNKNOWN | DrugDosageText | CC BY-NC | 33635018 | 19,289,501 | 2021-03 |
What was the outcome of reaction 'Cytomegalovirus hepatitis'? | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | Recovered | ReactionOutcome | CC BY-NC | 33635018 | 18,980,164 | 2021-03 |
What was the outcome of reaction 'Cytomegalovirus infection'? | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | Recovered | ReactionOutcome | CC BY-NC | 33635018 | 18,980,164 | 2021-03 |
What was the outcome of reaction 'Haemophagocytic lymphohistiocytosis'? | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | Recovered | ReactionOutcome | CC BY-NC | 33635018 | 18,980,164 | 2021-03 |
What was the outcome of reaction 'Hyperferritinaemia'? | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | Recovered | ReactionOutcome | CC BY-NC | 33635018 | 18,985,815 | 2021-03 |
What was the outcome of reaction 'Myelosuppression'? | Cytomegalovirus-Associated Hemophagocytic Syndrome Diagnosed by Liver Biopsy in a Kidney Transplant Recipient.
Hemophagocytic syndrome (HPS) is a rare but potentially life-threatening disease in kidney transplant recipients, and is caused by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen. Here, we report a 40-year-old male kidney transplant recipient who presented with fever, bicytopenia, and elevated liver enzymes 2 months after transplantation. Given that cytomegalovirus antigenemia and real-time polymerase chain reaction tests were positive, liver biopsy was performed under an assumption of cytomegalovirus-induced hepatitis. Hepatic histology revealed multifocal microabscess with cytomegalovirus inclusion bodies, marked Kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages. As laboratory findings such as hyperferritinemia, elevated serum lactate dehydrogenase, low natural killer cell activity, and high soluble interleukin-2 receptor were also compatible with HPS, the recipient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Following intravenous ganciclovir therapy with continuous administration of tacrolimus and corticosteroid, the symptoms resolved and laboratory findings were normalized. As far as we know, this is the first report of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that is diagnosed by liver biopsy.
INTRODUCTION
Hemophagocytic syndrome (HPS) is a clinicopathologic entity characterized by systemic proliferation of macrophages actively phagocytizing other blood cells in the bone marrow, lymph nodes, and the spleen.12 HPS is caused by impaired function of natural killer and cytotoxic T-cells leading to activation of macrophages.3 Overproduction of cytokines, including tumor necrosis factor alpha and interferon gamma, are also implicated in the pathogenesis of HPS that some of the symptoms are related to the cytokine overproduction.24 The most common clinical features of HPS include fever, hepatosplenomegaly, and cytopenia.5 HPS may develop in the context of genetic predisposition, infection, malignancy, and autoimmune disease.6 Most of all, viral infection, especially herpes virus infection, is the most frequent trigger of HPS both in healthy people and immunosuppressed patients.3
Cytomegalovirus infection is the single most frequent cause of infectious morbidity and mortality in kidney transplant recipients.78 However, cytomegalovirus-associated HPS has rarely been described in kidney transplant recipients since the first report of reactive HPS in kidney transplant recipient by Risdall, et al.910111213141516 In this rare disease, hepatic dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS. Here, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS in a kidney transplant recipient that was confirmed by hepatic histology.
CASE REPORT
A 40-year-old male received deceased donor kidney transplantation 8 years after starting hemodialysis due to IgA nephropathy. The immunosuppression regimen consisted of tacrolimus, corticosteroid, and mycophenolate mofetil (MMF) with induction therapy of basiliximab. Both donor and recipient were positive for IgG and negative for IgM of cytomegalovirus. The patient had an uneventful postoperative course with stable allograft function, and he was discharged on postoperative day 8. The prophylaxis for cytomegalovirus was not performed in the patient. Two months after transplantation, the patient was re-admitted for fever, epigastric discomfort, and mild weight loss. Physical examination was unremarkable with no evidence of hepatosplenomegaly or lymphadenopathy. The graft function remained stable with a serum creatinine of 1.04 mg/dL. Laboratory findings showed bicytopenia and mild liver enzymes elevation, but no other specific findings were observed.
At initial assessment, MMF-induced bone marrow suppression was suspected. With discontinuation of MMF and administration of granulocyte colony stimulating factor, absolute neutrophil count increased, but low grade fever persisted with continuous elevation of liver enzymes (Table 1). In addition to elevation of liver enzymes, the patient started to develop dyspnea, and computed tomography scan for lung showed bilateral lower lung ground glass opacity (Fig. 1). With an assumption of viral disease, several serological viral tests were performed. Serological studies for Epstein-Barr virus, BK virus, hepatitis A, B, and C, and human immunodeficiency virus were all negative, but active cytomegalovirus infection was confirmed by cytomegalovirus antigenemia and real-time polymerase chain reaction (a viral load of 216879 copies) tests. Under an assumption of cytomegalovirus-induced hepatitis, the patient underwent ultrasound-guided percutaneous gun biopsy of the liver. The liver biopsy showed multifocal microabscess including cytomegalovirus inclusion bodies, marked kupffer cell hyperplasia, and erythrophagocytosis by activated macrophages (Fig. 2), and the patient was diagnosed as having cytomegalovirus-induced hepatitis combined with reactive HPS. Additional tests showed hyperferritinemia, low natural killer cell activity, elevated serum lactate dehydrogenase, and high soluble interleukin-2 receptor, supporting our diagnosis of the patient.
On day 5 of admission, intravenous ganciclovir was started with continuous administration of tacrolimus and corticosteroid. In order to prevent additional bacterial infection and pneumonia aggravation, 4th generation cephalosporin was also started. On day 14 of admission, the patient's complete blood cell count and liver enzyme levels were nearly normalized, and serum ferritin declined to 656.0 µg/L. Two weeks after starting intravenous ganciclovir, the viral load of cytomegalovirus fell to 2617 copies, reaching below 150 copies by the time of discharge. As his symptoms were resolved and general condition improved, the recipient was discharged on day 26 after hospitalization. The patient was given oral valganciclovir (900 mg once daily) for an additional 3 months, and MMF was restarted 4 weeks after the discharge. As a screening exam for reactivation, cytomegalovirus antigenemia test was performed every 2 weeks for 3 months, and no reactivation occurred during the follow-up period. Informed consent was obtained from the patient regarding the publication of this case report.
DISCUSSION
HPS is a rare but potentially life-threatening disease in kidney transplant recipients, and it requires early diagnosis and initiation of treatment to improve clinical outcomes. However, its nonspecific clinical presentation makes the diagnosis challenging. In the present case, the patient presented with fever, epigastric discomfort, and mild weight loss. MMF-induced bone marrow suppression was initially suspected, but continuous increase of liver enzymes and positive cytomegalovirus serologic tests led us to perform liver biopsy under an assumption of cytomegalovirus-induced hepatitis. However, contrary to our expectation, the hepatic histology revealed marked Kupffer cell hyperplasia and erythrophagocytosis by activated macrophages, suggesting reactive HPS combined with cytomegalovirus-induced hepatitis. Subsequently, we conducted additional laboratory exams and were able to diagnosis HPS, as elevated serum ferritin, high soluble interleukin-2 receptor, and low natural killer cell activity were also compatible with HPS.
In kidney transplant recipients with HPS, liver dysfunction is often present, but liver biopsy has not been performed on the suspicion of HPS, since bone marrow analysis has been known to be the most sensitive diagnostic test for HPS.4 In the present case, however, a liver biopsy was performed instead of a bone marrow biopsy, as the patient's main problem was a continuous elevation of liver enzymes and HPS was not suspected at the time of performing liver biopsy. After the diagnosis of HPS, anti-viral agent was started and the patient's condition improved. Therefore, an additional bone marrow biopsy was not required to confirm HPS. To the best of our knowledge, this is the first report of cytomegalovirus-associated HPS that is diagnosed by liver biopsy in a kidney transplant recipient.
Since the spectrum of pathogens responsible for HPS is extremely broad, choosing the most adequate antiviral and antibacterial therapy is crucial. However, what to do with the immunosuppressive regimen still remains an unresolved issue.1 Immunosuppressive therapy may help in reducing the activation of macrophages and their cytokine production. On the other hand, the reduction or withdrawal of immunosuppressive therapy is needed to improve resistance to infection in kidney transplant recipients. According to Karras, et al.,4 who reported the largest series of HPS in kidney transplant recipients, majority of the patients experienced a life-threatening conditions including septic shock, acute respiratory distress syndrome, neurologic disorders, or cardiac failure. In these patients, immunosuppressive agents were tapered, with steroid monotherapy in some patients. In the present case, the patient managed to recover without the discontinuation of tacrolimus and corticosteroid. This suggests that, if the patient's disease severity is not severe, the administration of antiviral therapy with minimal withdrawal of immunosuppressive agent during treatment period would be sufficient to treat the cytomegalovirus-associated HPS in a kidney transplant patient.
Herein, we report a rare case of cytomegalovirus-induced hepatitis combined with reactive HPS that was confirmed by hepatic histology in a kidney transplant recipient. When a kidney transplant recipient presents with fever, cytopenia, and elevated liver enzymes, and positive cytomegalovirus serologic tests are confirmed, cytomegalovirus-associated HPS must be always suspected and liver biopsy may be considered for the early diagnosis and successful treatment of HPS.
Fig. 1 Computed tomography showing multiple ill-defined tiny nodules, ground glass opacity, peribronchiolar consolidation, and interlobular septal thickening in both lungs.
Fig. 2 Pathology results of liver biopsy. (A) Hematoxylin and eosin staininig showing multifocal microabscess, including cytomegalovirus inclusion bodies (star), and marked Kupffer cell hyperplasia with erythrophagocytosis (arrows) (×200). (B) Immunohistochemistry staining showing strong focal cytomegalovirus immunoreactivity with brownish areas (arrow) (×400).
Table 1 Changes in Laboratory Findings in the Patient
Normal range On admission After 4 days After 14 days
White blood cell count (/μL) 4000–11000 1800 6600 4700
Absolute neutrophil count (/μL) - 698.4 5940.0 1936.4
Hemoglobin (g/dL) 12.5–17.5 11.4 12.3 9.3
Platelet count (×104/μL) 13.4–38.7 6.5 7.4 17.3
Creatinine (mg/dL) 0.70–1.20 1.04 0.95 0.81
Alanine aminotransferase (U/L) 5–41 173 422 49
Aspartate aminotransferase (U/L) 5–40 190 560 42
Triglyceride (mg/dL) 37–200 N/A 190 125
Fibrinogen (mg/dL) 182–380 N/A 178 239
Lactate dehydrogenase (U/L) 100–200 N/A 647 N/A
Ferritin (μg/L) 30.0–400.0 N/A 6825.0 656.0
Natural killer cell activity (pg/mL) 251–6000 N/A 91 N/A
Soluble interleukin-2 receptor (U/mL) 158–623 N/A 2528.000 N/A
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS: Conceptualization: all authors.
Data curation: Eun Ji Choi, Jun Bae Bang, and Young Bae Kim.
Formal analysis: Eun Ji Choi and Jun Bae Bang.
Investigation: Eun Ji Choi and Jun Bae Bang.
Methodology: Eun Ji Choi and Jun Bae Bang.
Project administration: Chang-Kwon Oh and Su Hyung Lee.
Resources: Eun Ji Choi and Jun Bae Bang.
Software: Eun Ji Choi and Jun Bae Bang.
Supervision: Chang-Kwon Oh and Su Hyung Lee.
Validation: Eun Ji Choi and Jun Bae Bang.
Visualization: Eun Ji Choi and Jun Bae Bang.
Writing—original draft: Eun Ji Choi.
Writing—review & editing: Jun Bae Bang.
Approval of final manuscript: all authors. | Recovering | ReactionOutcome | CC BY-NC | 33635018 | 18,985,815 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute graft versus host disease'. | Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia.
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
pmcIntroduction
Infections remain the most important cause of death in an oncohematological settings, and the spectrum of pathogens is vast and increases concomitantly with immunosuppression.1 Empirical therapies are frequently indicated but with several limitations: overuse of antimicrobials, emergency of antimicrobial resistance, adverse events, and risk of failure. The delay in diagnosis implies a delay in starting appropriate therapy and worse outcomes. Traditional tests based on cultures, biological methods, and serological tests are time-consuming and sometimes are not sufficient to diagnose several infectious complications on hematological patients. Therefore, alternative methodologies are needed for a prompt and correct diagnosis.2, 3
Next-generation metagenomic sequencing (mNGS) has been applied in several scenarios: sepsis, meningitis and encephalitis, bloodstream infection, pneumonia, and others. In these situations, routine microbiologic testing is frequently insufficient to detect uncommon pathogens, making sequencing an attractive approach for the detection of a high number of pathogens in a single platform. This characteristic also contributes to significantly decrease the turnaround time for the result, helping to expedite initiation of an adequate treatment and to have a better outcome.2, 3
Case reports
Case 1
A 38-year-old female with acute myeloid leukemia achieved complete response following induction of remission (cytarabine and daunorubicin) and two consolidations with high dose cytarabine. She developed febrile neutropenia in all chemotherapy cycles without microbiological documentation. Antifungal prophylaxis with fluconazole was given in the first and second cycles. Three months after the last consolidation cycle, she developed fever and malaise. No findings in the clinical exam were noted, and blood cultures were negative. An abdominal CT scan documented solid lesions in the liver. Voriconazole was started to cover chronic disseminated candidiasis, and liver biopsy was performed. In tissue, there was a mixed non-granulomatous inflammatory infiltrate without neoplasia, fungal, or bacterial elements. After two months of voriconazole, symptoms remained, and new solid lesions were noted in the liver and spleen by CT scan. A second liver biopsy was performed, but the culture remained negative. Antifungal was modified empirically to caspofungin, and a sample of blood was collected to perform mNGS (Karius® test). The test was performed by Karius Laboratory (Karius, Redwood City, CA). The standard mNGS protocol is briefly described. During an acute infection, pathogens leave microbial cell-free DNA (cfDNA) in blood. mNGS workflow starts with nucleic acid extraction of the clinical sample, library preparation, and NGS sequencing. Reads are the basic element produced by DNA sequencing. All DNA of a specimen is sequenced in parallel, resulting in isolation and amplification of both host and pathogen nucleic acid sequenced from the sample. The microbial reads were analyzed to identify the composition and abundance of reads of organisms present after removing host DNA from microbial DNA. Results displayed the concentration of pathogen cfDNA detected per microliter of plasma.3 The concentration of each microorganism was compared to the same microorganism's concentration(s) reported in the last 1000 specimens tested by Karius. The mNGS test revealed Candida tropicalis. Caspofungin was maintained, and three months after, symptoms disappeared, and there was a significant reduction in all lesions.
Case 2
A 46-year-old male with a T acute lymphoid leukemia entered a complete remission following induction therapy and received an unrelated allogeneic stem cell transplant (UNR-SCT). Before the transplant, no important infectious event was documented. UNR-SCT conditioning regimen was cyclophosphamide, thymoglobulin, and total body irradiation. During the SCT-neutropenic phase, he developed febrile neutropenia, with negative blood cultures, and was treated empirically with cefepime and vancomycin with a rapid resolution of fever. The patient recovered from neutropenia after 14 days, but a daily fever started after neutrophil recovery. A tiny filamentous in the mitral valve was observed by echocardiography. Empirical therapy with meropenem and daptomycin was started. Concomitantly, acute graft-versus-host disease (GVHD) was noted in the skin and hepatic markers worsened. A few days after, the patient developed acute respiratory failure with a diffuse pulmonary infiltrate by CT scan. Liposomal amphotericin and trimethoprim-sulfamethoxazole (TMP-SMX) were added to therapy. An endemic coronavirus (HKU1) was identified by multiplex-PCR in bronchoalveolar lavage (BAL). Cultures, Galactomannan, Pneumocystis jirovecii-, and tuberculosis-PCR in BAL were negative. At this time, the patient started altering mental status, but the magnetic resonance imaging (MRI) did not reveal any change. A blood sample was collected for mNGS and revealed the presence of Toxoplasma gondii, and TMP-SMX therapy was maintained. New transesophageal echocardiography was performed, and the previous mitral findings were no longer observed. Unfortunately, during toxoplasmosis treatment, the patient developed sepsis due to multiresistant Acinetobacter baumanni in the following days and died. The patient was T. gondii-seropositive (positive IgG and negative IgM) before the transplant.
Case 3
A 34-year-old female with acute lymphoid leukemia in remission received a haploidentical peripheral allogeneic STC (Haplo-SCT) from her brother following conditioning with cyclophosphamide, fludarabine, and total body irradiation. Febrile neutropenia developed during SCT-neutropenic phase, and she was initially treated with empirical cefepime and switched to meropenem and vancomycin due to the persistence of fever despite negative cultures. Neutropenia recovered 16 days after transplantation. On day +18, the patient reported urinary symptoms and gross hematuria. CMV disease was documented (CMV inclusion bodies in bladder tissue and CMV viremia), and ganciclovir was started. Cultures and molecular tests for other viruses (adenovirus, BK, and JC) were negative in urine samples. During ganciclovir therapy, CMV viremia was resolved, but hematuria persisted. Two weeks after, the patient started fever and respiratory symptoms. Nodules, ground-glass infiltrates, and pleural effusion were observed by CT scan. Liposomal amphotericin was started empirically, with a resolution of fever, respiratory symptoms, and radiological improvement. Bronchoalveolar lavage was negative for CMV, galactomannan assay, fungal and bacterial cultures. On D + 60, GVHD was noted in the skin and liver, and corticosteroid was started. Three weeks later, the patient experienced new episodes of fever with moderate to severe respiratory symptoms. A new CT scan showed bilateral infiltrates, centrilobular opacities, and consolidations. Empirical therapies were then restarted, and a sample of blood collected to perform mNGS. Bacterial and fungal cultures, toxoplasmosis, legionella, pneumocystis, and CMV molecular tests were all negative. The mNGS was positive for adenovirus and torque teno virus (TTV). Cidofovir was started, but the patient developed sepsis, renal and respiratory failure, and in a few days, worsened with hemodynamic instability and died.
Discussion
Patients submitted to acute leukemia treatment have considerable risk of infection.1 Although bacterial and fungi etiologies are most frequent, some diagnostically challenging infections occur and require an intensive investigation and a large diagnostical panel. Intense immunosuppression, dense antimicrobial exposure, and emergency of uncommon agents are important factors related to these diagnostically challenging events. In this report, we summarized three patients with acute leukemia in different phases of therapy with complicated, challenging infections. All of them have had their diagnoses based on mNGS (Karius® test) after an intensive laboratory and imaging investigation with no elucidative diagnosis. The Karius® test is a mNGS of microbial cell-free-DNA able to identify and quantify over 1000 clinically relevant pathogens, including bacteria, fungi, parasites, and DNA viruses. It does not cover RNA viruses nor bacterial resistance profiles. Karius reports the concentration of pathogen cfDNA detected per microliter (MPM). As there is no threshold to distinguish colonization from infection, a committee reviewed all results considering MPM, medical history, physical findings, and conventional laboratory tests to confirm if the result was clinically significant.
The first case presented chronic disseminated candidiasis, a rare presentation of invasive fungal infection in acute leukemia patients nowadays.4, 5 Despite considering invasive fungal infection the probable diagnosis, it was not confirmed by tissue cultures, and the patient experienced radiological progression despite antifungal therapy. Therefore, the mNGS test was useful for confirming the diagnosis and identifying the Candida species, which allowed antifungal therapy adjustment and patient’s recovery.
In the second case, the mNGS detected an uncommon infection in SCT. Incidence of toxoplasmosis reactivation after SCT is considered rare, depending on the country's prevalence of toxoplasmosis.6 In Brazil, toxoplasmosis seroprevalence is very high, and TMP-SMX prophylaxis is regularly used in the post-SCT period. Despite the absence of tissue documentation, the mNGS contributed to confirm the etiology leading to adequate therapy. Unfortunately, the patient developed a second infection complication, and death occurred within 30 days after toxoplasmosis diagnosis. Mortality rates of toxoplasmosis in SCT patients are reported as 50% or higher by some studies.6, 7
In the last case, mNGS detected disseminated adenoviruses and a recently described virus. Adenovirus can cause a devasting disease in SCT patients. Hemorrhagic cystitis, pneumonia, enteritis, and hepatitis are clinical manifestations of invasive adenovirus, especially after high immunosuppression SCT.8 Torque teno virus (TTV) DNA is commonly found in the plasma of healthy blood donors being considered a non-pathogenic member of the human virome.9 TTV viremia has been evaluated as a surrogate marker of immune function.10
Although mNGS has been applied in several scenarios, some mNGS reports published in leukemia patients showed a contribution considering the broad spectrum of diagnosis possibilities and the consequence of infectious complications in immunocompromised hosts.11, 12
In this study, mNGS obtained from patients with acute leukemia improved the diagnosis of challenging infection diseases and provided the opportunity for adequate therapy.
Ethics approval
This study was approved by the institutional review borders of Hospital 9 de Julho (reference Number: 30907420.1.0000.5455).
Conflicts of interest
The authors declare no conflicts of interest.
Authors contributions
MG, PVO, and MM were involved in the clinical management of patients. LCP, and AC were involved in laboratorial diagnosis. This manuscript was initially drafted by MG, LCP, and AC and then revised by other authors in the study. All authors read and approved the final manuscript.
Acknowledgments
The authors thank R Luz, MR Valentim, J Ramos, JE Levi, for their essential contribution. | DAPTOMYCIN, MEROPENEM | DrugsGivenReaction | CC BY-NC-ND | 33639095 | 19,806,447 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory failure'. | Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia.
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
pmcIntroduction
Infections remain the most important cause of death in an oncohematological settings, and the spectrum of pathogens is vast and increases concomitantly with immunosuppression.1 Empirical therapies are frequently indicated but with several limitations: overuse of antimicrobials, emergency of antimicrobial resistance, adverse events, and risk of failure. The delay in diagnosis implies a delay in starting appropriate therapy and worse outcomes. Traditional tests based on cultures, biological methods, and serological tests are time-consuming and sometimes are not sufficient to diagnose several infectious complications on hematological patients. Therefore, alternative methodologies are needed for a prompt and correct diagnosis.2, 3
Next-generation metagenomic sequencing (mNGS) has been applied in several scenarios: sepsis, meningitis and encephalitis, bloodstream infection, pneumonia, and others. In these situations, routine microbiologic testing is frequently insufficient to detect uncommon pathogens, making sequencing an attractive approach for the detection of a high number of pathogens in a single platform. This characteristic also contributes to significantly decrease the turnaround time for the result, helping to expedite initiation of an adequate treatment and to have a better outcome.2, 3
Case reports
Case 1
A 38-year-old female with acute myeloid leukemia achieved complete response following induction of remission (cytarabine and daunorubicin) and two consolidations with high dose cytarabine. She developed febrile neutropenia in all chemotherapy cycles without microbiological documentation. Antifungal prophylaxis with fluconazole was given in the first and second cycles. Three months after the last consolidation cycle, she developed fever and malaise. No findings in the clinical exam were noted, and blood cultures were negative. An abdominal CT scan documented solid lesions in the liver. Voriconazole was started to cover chronic disseminated candidiasis, and liver biopsy was performed. In tissue, there was a mixed non-granulomatous inflammatory infiltrate without neoplasia, fungal, or bacterial elements. After two months of voriconazole, symptoms remained, and new solid lesions were noted in the liver and spleen by CT scan. A second liver biopsy was performed, but the culture remained negative. Antifungal was modified empirically to caspofungin, and a sample of blood was collected to perform mNGS (Karius® test). The test was performed by Karius Laboratory (Karius, Redwood City, CA). The standard mNGS protocol is briefly described. During an acute infection, pathogens leave microbial cell-free DNA (cfDNA) in blood. mNGS workflow starts with nucleic acid extraction of the clinical sample, library preparation, and NGS sequencing. Reads are the basic element produced by DNA sequencing. All DNA of a specimen is sequenced in parallel, resulting in isolation and amplification of both host and pathogen nucleic acid sequenced from the sample. The microbial reads were analyzed to identify the composition and abundance of reads of organisms present after removing host DNA from microbial DNA. Results displayed the concentration of pathogen cfDNA detected per microliter of plasma.3 The concentration of each microorganism was compared to the same microorganism's concentration(s) reported in the last 1000 specimens tested by Karius. The mNGS test revealed Candida tropicalis. Caspofungin was maintained, and three months after, symptoms disappeared, and there was a significant reduction in all lesions.
Case 2
A 46-year-old male with a T acute lymphoid leukemia entered a complete remission following induction therapy and received an unrelated allogeneic stem cell transplant (UNR-SCT). Before the transplant, no important infectious event was documented. UNR-SCT conditioning regimen was cyclophosphamide, thymoglobulin, and total body irradiation. During the SCT-neutropenic phase, he developed febrile neutropenia, with negative blood cultures, and was treated empirically with cefepime and vancomycin with a rapid resolution of fever. The patient recovered from neutropenia after 14 days, but a daily fever started after neutrophil recovery. A tiny filamentous in the mitral valve was observed by echocardiography. Empirical therapy with meropenem and daptomycin was started. Concomitantly, acute graft-versus-host disease (GVHD) was noted in the skin and hepatic markers worsened. A few days after, the patient developed acute respiratory failure with a diffuse pulmonary infiltrate by CT scan. Liposomal amphotericin and trimethoprim-sulfamethoxazole (TMP-SMX) were added to therapy. An endemic coronavirus (HKU1) was identified by multiplex-PCR in bronchoalveolar lavage (BAL). Cultures, Galactomannan, Pneumocystis jirovecii-, and tuberculosis-PCR in BAL were negative. At this time, the patient started altering mental status, but the magnetic resonance imaging (MRI) did not reveal any change. A blood sample was collected for mNGS and revealed the presence of Toxoplasma gondii, and TMP-SMX therapy was maintained. New transesophageal echocardiography was performed, and the previous mitral findings were no longer observed. Unfortunately, during toxoplasmosis treatment, the patient developed sepsis due to multiresistant Acinetobacter baumanni in the following days and died. The patient was T. gondii-seropositive (positive IgG and negative IgM) before the transplant.
Case 3
A 34-year-old female with acute lymphoid leukemia in remission received a haploidentical peripheral allogeneic STC (Haplo-SCT) from her brother following conditioning with cyclophosphamide, fludarabine, and total body irradiation. Febrile neutropenia developed during SCT-neutropenic phase, and she was initially treated with empirical cefepime and switched to meropenem and vancomycin due to the persistence of fever despite negative cultures. Neutropenia recovered 16 days after transplantation. On day +18, the patient reported urinary symptoms and gross hematuria. CMV disease was documented (CMV inclusion bodies in bladder tissue and CMV viremia), and ganciclovir was started. Cultures and molecular tests for other viruses (adenovirus, BK, and JC) were negative in urine samples. During ganciclovir therapy, CMV viremia was resolved, but hematuria persisted. Two weeks after, the patient started fever and respiratory symptoms. Nodules, ground-glass infiltrates, and pleural effusion were observed by CT scan. Liposomal amphotericin was started empirically, with a resolution of fever, respiratory symptoms, and radiological improvement. Bronchoalveolar lavage was negative for CMV, galactomannan assay, fungal and bacterial cultures. On D + 60, GVHD was noted in the skin and liver, and corticosteroid was started. Three weeks later, the patient experienced new episodes of fever with moderate to severe respiratory symptoms. A new CT scan showed bilateral infiltrates, centrilobular opacities, and consolidations. Empirical therapies were then restarted, and a sample of blood collected to perform mNGS. Bacterial and fungal cultures, toxoplasmosis, legionella, pneumocystis, and CMV molecular tests were all negative. The mNGS was positive for adenovirus and torque teno virus (TTV). Cidofovir was started, but the patient developed sepsis, renal and respiratory failure, and in a few days, worsened with hemodynamic instability and died.
Discussion
Patients submitted to acute leukemia treatment have considerable risk of infection.1 Although bacterial and fungi etiologies are most frequent, some diagnostically challenging infections occur and require an intensive investigation and a large diagnostical panel. Intense immunosuppression, dense antimicrobial exposure, and emergency of uncommon agents are important factors related to these diagnostically challenging events. In this report, we summarized three patients with acute leukemia in different phases of therapy with complicated, challenging infections. All of them have had their diagnoses based on mNGS (Karius® test) after an intensive laboratory and imaging investigation with no elucidative diagnosis. The Karius® test is a mNGS of microbial cell-free-DNA able to identify and quantify over 1000 clinically relevant pathogens, including bacteria, fungi, parasites, and DNA viruses. It does not cover RNA viruses nor bacterial resistance profiles. Karius reports the concentration of pathogen cfDNA detected per microliter (MPM). As there is no threshold to distinguish colonization from infection, a committee reviewed all results considering MPM, medical history, physical findings, and conventional laboratory tests to confirm if the result was clinically significant.
The first case presented chronic disseminated candidiasis, a rare presentation of invasive fungal infection in acute leukemia patients nowadays.4, 5 Despite considering invasive fungal infection the probable diagnosis, it was not confirmed by tissue cultures, and the patient experienced radiological progression despite antifungal therapy. Therefore, the mNGS test was useful for confirming the diagnosis and identifying the Candida species, which allowed antifungal therapy adjustment and patient’s recovery.
In the second case, the mNGS detected an uncommon infection in SCT. Incidence of toxoplasmosis reactivation after SCT is considered rare, depending on the country's prevalence of toxoplasmosis.6 In Brazil, toxoplasmosis seroprevalence is very high, and TMP-SMX prophylaxis is regularly used in the post-SCT period. Despite the absence of tissue documentation, the mNGS contributed to confirm the etiology leading to adequate therapy. Unfortunately, the patient developed a second infection complication, and death occurred within 30 days after toxoplasmosis diagnosis. Mortality rates of toxoplasmosis in SCT patients are reported as 50% or higher by some studies.6, 7
In the last case, mNGS detected disseminated adenoviruses and a recently described virus. Adenovirus can cause a devasting disease in SCT patients. Hemorrhagic cystitis, pneumonia, enteritis, and hepatitis are clinical manifestations of invasive adenovirus, especially after high immunosuppression SCT.8 Torque teno virus (TTV) DNA is commonly found in the plasma of healthy blood donors being considered a non-pathogenic member of the human virome.9 TTV viremia has been evaluated as a surrogate marker of immune function.10
Although mNGS has been applied in several scenarios, some mNGS reports published in leukemia patients showed a contribution considering the broad spectrum of diagnosis possibilities and the consequence of infectious complications in immunocompromised hosts.11, 12
In this study, mNGS obtained from patients with acute leukemia improved the diagnosis of challenging infection diseases and provided the opportunity for adequate therapy.
Ethics approval
This study was approved by the institutional review borders of Hospital 9 de Julho (reference Number: 30907420.1.0000.5455).
Conflicts of interest
The authors declare no conflicts of interest.
Authors contributions
MG, PVO, and MM were involved in the clinical management of patients. LCP, and AC were involved in laboratorial diagnosis. This manuscript was initially drafted by MG, LCP, and AC and then revised by other authors in the study. All authors read and approved the final manuscript.
Acknowledgments
The authors thank R Luz, MR Valentim, J Ramos, JE Levi, for their essential contribution. | DAPTOMYCIN, MEROPENEM | DrugsGivenReaction | CC BY-NC-ND | 33639095 | 19,806,447 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia.
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
pmcIntroduction
Infections remain the most important cause of death in an oncohematological settings, and the spectrum of pathogens is vast and increases concomitantly with immunosuppression.1 Empirical therapies are frequently indicated but with several limitations: overuse of antimicrobials, emergency of antimicrobial resistance, adverse events, and risk of failure. The delay in diagnosis implies a delay in starting appropriate therapy and worse outcomes. Traditional tests based on cultures, biological methods, and serological tests are time-consuming and sometimes are not sufficient to diagnose several infectious complications on hematological patients. Therefore, alternative methodologies are needed for a prompt and correct diagnosis.2, 3
Next-generation metagenomic sequencing (mNGS) has been applied in several scenarios: sepsis, meningitis and encephalitis, bloodstream infection, pneumonia, and others. In these situations, routine microbiologic testing is frequently insufficient to detect uncommon pathogens, making sequencing an attractive approach for the detection of a high number of pathogens in a single platform. This characteristic also contributes to significantly decrease the turnaround time for the result, helping to expedite initiation of an adequate treatment and to have a better outcome.2, 3
Case reports
Case 1
A 38-year-old female with acute myeloid leukemia achieved complete response following induction of remission (cytarabine and daunorubicin) and two consolidations with high dose cytarabine. She developed febrile neutropenia in all chemotherapy cycles without microbiological documentation. Antifungal prophylaxis with fluconazole was given in the first and second cycles. Three months after the last consolidation cycle, she developed fever and malaise. No findings in the clinical exam were noted, and blood cultures were negative. An abdominal CT scan documented solid lesions in the liver. Voriconazole was started to cover chronic disseminated candidiasis, and liver biopsy was performed. In tissue, there was a mixed non-granulomatous inflammatory infiltrate without neoplasia, fungal, or bacterial elements. After two months of voriconazole, symptoms remained, and new solid lesions were noted in the liver and spleen by CT scan. A second liver biopsy was performed, but the culture remained negative. Antifungal was modified empirically to caspofungin, and a sample of blood was collected to perform mNGS (Karius® test). The test was performed by Karius Laboratory (Karius, Redwood City, CA). The standard mNGS protocol is briefly described. During an acute infection, pathogens leave microbial cell-free DNA (cfDNA) in blood. mNGS workflow starts with nucleic acid extraction of the clinical sample, library preparation, and NGS sequencing. Reads are the basic element produced by DNA sequencing. All DNA of a specimen is sequenced in parallel, resulting in isolation and amplification of both host and pathogen nucleic acid sequenced from the sample. The microbial reads were analyzed to identify the composition and abundance of reads of organisms present after removing host DNA from microbial DNA. Results displayed the concentration of pathogen cfDNA detected per microliter of plasma.3 The concentration of each microorganism was compared to the same microorganism's concentration(s) reported in the last 1000 specimens tested by Karius. The mNGS test revealed Candida tropicalis. Caspofungin was maintained, and three months after, symptoms disappeared, and there was a significant reduction in all lesions.
Case 2
A 46-year-old male with a T acute lymphoid leukemia entered a complete remission following induction therapy and received an unrelated allogeneic stem cell transplant (UNR-SCT). Before the transplant, no important infectious event was documented. UNR-SCT conditioning regimen was cyclophosphamide, thymoglobulin, and total body irradiation. During the SCT-neutropenic phase, he developed febrile neutropenia, with negative blood cultures, and was treated empirically with cefepime and vancomycin with a rapid resolution of fever. The patient recovered from neutropenia after 14 days, but a daily fever started after neutrophil recovery. A tiny filamentous in the mitral valve was observed by echocardiography. Empirical therapy with meropenem and daptomycin was started. Concomitantly, acute graft-versus-host disease (GVHD) was noted in the skin and hepatic markers worsened. A few days after, the patient developed acute respiratory failure with a diffuse pulmonary infiltrate by CT scan. Liposomal amphotericin and trimethoprim-sulfamethoxazole (TMP-SMX) were added to therapy. An endemic coronavirus (HKU1) was identified by multiplex-PCR in bronchoalveolar lavage (BAL). Cultures, Galactomannan, Pneumocystis jirovecii-, and tuberculosis-PCR in BAL were negative. At this time, the patient started altering mental status, but the magnetic resonance imaging (MRI) did not reveal any change. A blood sample was collected for mNGS and revealed the presence of Toxoplasma gondii, and TMP-SMX therapy was maintained. New transesophageal echocardiography was performed, and the previous mitral findings were no longer observed. Unfortunately, during toxoplasmosis treatment, the patient developed sepsis due to multiresistant Acinetobacter baumanni in the following days and died. The patient was T. gondii-seropositive (positive IgG and negative IgM) before the transplant.
Case 3
A 34-year-old female with acute lymphoid leukemia in remission received a haploidentical peripheral allogeneic STC (Haplo-SCT) from her brother following conditioning with cyclophosphamide, fludarabine, and total body irradiation. Febrile neutropenia developed during SCT-neutropenic phase, and she was initially treated with empirical cefepime and switched to meropenem and vancomycin due to the persistence of fever despite negative cultures. Neutropenia recovered 16 days after transplantation. On day +18, the patient reported urinary symptoms and gross hematuria. CMV disease was documented (CMV inclusion bodies in bladder tissue and CMV viremia), and ganciclovir was started. Cultures and molecular tests for other viruses (adenovirus, BK, and JC) were negative in urine samples. During ganciclovir therapy, CMV viremia was resolved, but hematuria persisted. Two weeks after, the patient started fever and respiratory symptoms. Nodules, ground-glass infiltrates, and pleural effusion were observed by CT scan. Liposomal amphotericin was started empirically, with a resolution of fever, respiratory symptoms, and radiological improvement. Bronchoalveolar lavage was negative for CMV, galactomannan assay, fungal and bacterial cultures. On D + 60, GVHD was noted in the skin and liver, and corticosteroid was started. Three weeks later, the patient experienced new episodes of fever with moderate to severe respiratory symptoms. A new CT scan showed bilateral infiltrates, centrilobular opacities, and consolidations. Empirical therapies were then restarted, and a sample of blood collected to perform mNGS. Bacterial and fungal cultures, toxoplasmosis, legionella, pneumocystis, and CMV molecular tests were all negative. The mNGS was positive for adenovirus and torque teno virus (TTV). Cidofovir was started, but the patient developed sepsis, renal and respiratory failure, and in a few days, worsened with hemodynamic instability and died.
Discussion
Patients submitted to acute leukemia treatment have considerable risk of infection.1 Although bacterial and fungi etiologies are most frequent, some diagnostically challenging infections occur and require an intensive investigation and a large diagnostical panel. Intense immunosuppression, dense antimicrobial exposure, and emergency of uncommon agents are important factors related to these diagnostically challenging events. In this report, we summarized three patients with acute leukemia in different phases of therapy with complicated, challenging infections. All of them have had their diagnoses based on mNGS (Karius® test) after an intensive laboratory and imaging investigation with no elucidative diagnosis. The Karius® test is a mNGS of microbial cell-free-DNA able to identify and quantify over 1000 clinically relevant pathogens, including bacteria, fungi, parasites, and DNA viruses. It does not cover RNA viruses nor bacterial resistance profiles. Karius reports the concentration of pathogen cfDNA detected per microliter (MPM). As there is no threshold to distinguish colonization from infection, a committee reviewed all results considering MPM, medical history, physical findings, and conventional laboratory tests to confirm if the result was clinically significant.
The first case presented chronic disseminated candidiasis, a rare presentation of invasive fungal infection in acute leukemia patients nowadays.4, 5 Despite considering invasive fungal infection the probable diagnosis, it was not confirmed by tissue cultures, and the patient experienced radiological progression despite antifungal therapy. Therefore, the mNGS test was useful for confirming the diagnosis and identifying the Candida species, which allowed antifungal therapy adjustment and patient’s recovery.
In the second case, the mNGS detected an uncommon infection in SCT. Incidence of toxoplasmosis reactivation after SCT is considered rare, depending on the country's prevalence of toxoplasmosis.6 In Brazil, toxoplasmosis seroprevalence is very high, and TMP-SMX prophylaxis is regularly used in the post-SCT period. Despite the absence of tissue documentation, the mNGS contributed to confirm the etiology leading to adequate therapy. Unfortunately, the patient developed a second infection complication, and death occurred within 30 days after toxoplasmosis diagnosis. Mortality rates of toxoplasmosis in SCT patients are reported as 50% or higher by some studies.6, 7
In the last case, mNGS detected disseminated adenoviruses and a recently described virus. Adenovirus can cause a devasting disease in SCT patients. Hemorrhagic cystitis, pneumonia, enteritis, and hepatitis are clinical manifestations of invasive adenovirus, especially after high immunosuppression SCT.8 Torque teno virus (TTV) DNA is commonly found in the plasma of healthy blood donors being considered a non-pathogenic member of the human virome.9 TTV viremia has been evaluated as a surrogate marker of immune function.10
Although mNGS has been applied in several scenarios, some mNGS reports published in leukemia patients showed a contribution considering the broad spectrum of diagnosis possibilities and the consequence of infectious complications in immunocompromised hosts.11, 12
In this study, mNGS obtained from patients with acute leukemia improved the diagnosis of challenging infection diseases and provided the opportunity for adequate therapy.
Ethics approval
This study was approved by the institutional review borders of Hospital 9 de Julho (reference Number: 30907420.1.0000.5455).
Conflicts of interest
The authors declare no conflicts of interest.
Authors contributions
MG, PVO, and MM were involved in the clinical management of patients. LCP, and AC were involved in laboratorial diagnosis. This manuscript was initially drafted by MG, LCP, and AC and then revised by other authors in the study. All authors read and approved the final manuscript.
Acknowledgments
The authors thank R Luz, MR Valentim, J Ramos, JE Levi, for their essential contribution. | DAPTOMYCIN, MEROPENEM | DrugsGivenReaction | CC BY-NC-ND | 33639095 | 19,806,447 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia.
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
pmcIntroduction
Infections remain the most important cause of death in an oncohematological settings, and the spectrum of pathogens is vast and increases concomitantly with immunosuppression.1 Empirical therapies are frequently indicated but with several limitations: overuse of antimicrobials, emergency of antimicrobial resistance, adverse events, and risk of failure. The delay in diagnosis implies a delay in starting appropriate therapy and worse outcomes. Traditional tests based on cultures, biological methods, and serological tests are time-consuming and sometimes are not sufficient to diagnose several infectious complications on hematological patients. Therefore, alternative methodologies are needed for a prompt and correct diagnosis.2, 3
Next-generation metagenomic sequencing (mNGS) has been applied in several scenarios: sepsis, meningitis and encephalitis, bloodstream infection, pneumonia, and others. In these situations, routine microbiologic testing is frequently insufficient to detect uncommon pathogens, making sequencing an attractive approach for the detection of a high number of pathogens in a single platform. This characteristic also contributes to significantly decrease the turnaround time for the result, helping to expedite initiation of an adequate treatment and to have a better outcome.2, 3
Case reports
Case 1
A 38-year-old female with acute myeloid leukemia achieved complete response following induction of remission (cytarabine and daunorubicin) and two consolidations with high dose cytarabine. She developed febrile neutropenia in all chemotherapy cycles without microbiological documentation. Antifungal prophylaxis with fluconazole was given in the first and second cycles. Three months after the last consolidation cycle, she developed fever and malaise. No findings in the clinical exam were noted, and blood cultures were negative. An abdominal CT scan documented solid lesions in the liver. Voriconazole was started to cover chronic disseminated candidiasis, and liver biopsy was performed. In tissue, there was a mixed non-granulomatous inflammatory infiltrate without neoplasia, fungal, or bacterial elements. After two months of voriconazole, symptoms remained, and new solid lesions were noted in the liver and spleen by CT scan. A second liver biopsy was performed, but the culture remained negative. Antifungal was modified empirically to caspofungin, and a sample of blood was collected to perform mNGS (Karius® test). The test was performed by Karius Laboratory (Karius, Redwood City, CA). The standard mNGS protocol is briefly described. During an acute infection, pathogens leave microbial cell-free DNA (cfDNA) in blood. mNGS workflow starts with nucleic acid extraction of the clinical sample, library preparation, and NGS sequencing. Reads are the basic element produced by DNA sequencing. All DNA of a specimen is sequenced in parallel, resulting in isolation and amplification of both host and pathogen nucleic acid sequenced from the sample. The microbial reads were analyzed to identify the composition and abundance of reads of organisms present after removing host DNA from microbial DNA. Results displayed the concentration of pathogen cfDNA detected per microliter of plasma.3 The concentration of each microorganism was compared to the same microorganism's concentration(s) reported in the last 1000 specimens tested by Karius. The mNGS test revealed Candida tropicalis. Caspofungin was maintained, and three months after, symptoms disappeared, and there was a significant reduction in all lesions.
Case 2
A 46-year-old male with a T acute lymphoid leukemia entered a complete remission following induction therapy and received an unrelated allogeneic stem cell transplant (UNR-SCT). Before the transplant, no important infectious event was documented. UNR-SCT conditioning regimen was cyclophosphamide, thymoglobulin, and total body irradiation. During the SCT-neutropenic phase, he developed febrile neutropenia, with negative blood cultures, and was treated empirically with cefepime and vancomycin with a rapid resolution of fever. The patient recovered from neutropenia after 14 days, but a daily fever started after neutrophil recovery. A tiny filamentous in the mitral valve was observed by echocardiography. Empirical therapy with meropenem and daptomycin was started. Concomitantly, acute graft-versus-host disease (GVHD) was noted in the skin and hepatic markers worsened. A few days after, the patient developed acute respiratory failure with a diffuse pulmonary infiltrate by CT scan. Liposomal amphotericin and trimethoprim-sulfamethoxazole (TMP-SMX) were added to therapy. An endemic coronavirus (HKU1) was identified by multiplex-PCR in bronchoalveolar lavage (BAL). Cultures, Galactomannan, Pneumocystis jirovecii-, and tuberculosis-PCR in BAL were negative. At this time, the patient started altering mental status, but the magnetic resonance imaging (MRI) did not reveal any change. A blood sample was collected for mNGS and revealed the presence of Toxoplasma gondii, and TMP-SMX therapy was maintained. New transesophageal echocardiography was performed, and the previous mitral findings were no longer observed. Unfortunately, during toxoplasmosis treatment, the patient developed sepsis due to multiresistant Acinetobacter baumanni in the following days and died. The patient was T. gondii-seropositive (positive IgG and negative IgM) before the transplant.
Case 3
A 34-year-old female with acute lymphoid leukemia in remission received a haploidentical peripheral allogeneic STC (Haplo-SCT) from her brother following conditioning with cyclophosphamide, fludarabine, and total body irradiation. Febrile neutropenia developed during SCT-neutropenic phase, and she was initially treated with empirical cefepime and switched to meropenem and vancomycin due to the persistence of fever despite negative cultures. Neutropenia recovered 16 days after transplantation. On day +18, the patient reported urinary symptoms and gross hematuria. CMV disease was documented (CMV inclusion bodies in bladder tissue and CMV viremia), and ganciclovir was started. Cultures and molecular tests for other viruses (adenovirus, BK, and JC) were negative in urine samples. During ganciclovir therapy, CMV viremia was resolved, but hematuria persisted. Two weeks after, the patient started fever and respiratory symptoms. Nodules, ground-glass infiltrates, and pleural effusion were observed by CT scan. Liposomal amphotericin was started empirically, with a resolution of fever, respiratory symptoms, and radiological improvement. Bronchoalveolar lavage was negative for CMV, galactomannan assay, fungal and bacterial cultures. On D + 60, GVHD was noted in the skin and liver, and corticosteroid was started. Three weeks later, the patient experienced new episodes of fever with moderate to severe respiratory symptoms. A new CT scan showed bilateral infiltrates, centrilobular opacities, and consolidations. Empirical therapies were then restarted, and a sample of blood collected to perform mNGS. Bacterial and fungal cultures, toxoplasmosis, legionella, pneumocystis, and CMV molecular tests were all negative. The mNGS was positive for adenovirus and torque teno virus (TTV). Cidofovir was started, but the patient developed sepsis, renal and respiratory failure, and in a few days, worsened with hemodynamic instability and died.
Discussion
Patients submitted to acute leukemia treatment have considerable risk of infection.1 Although bacterial and fungi etiologies are most frequent, some diagnostically challenging infections occur and require an intensive investigation and a large diagnostical panel. Intense immunosuppression, dense antimicrobial exposure, and emergency of uncommon agents are important factors related to these diagnostically challenging events. In this report, we summarized three patients with acute leukemia in different phases of therapy with complicated, challenging infections. All of them have had their diagnoses based on mNGS (Karius® test) after an intensive laboratory and imaging investigation with no elucidative diagnosis. The Karius® test is a mNGS of microbial cell-free-DNA able to identify and quantify over 1000 clinically relevant pathogens, including bacteria, fungi, parasites, and DNA viruses. It does not cover RNA viruses nor bacterial resistance profiles. Karius reports the concentration of pathogen cfDNA detected per microliter (MPM). As there is no threshold to distinguish colonization from infection, a committee reviewed all results considering MPM, medical history, physical findings, and conventional laboratory tests to confirm if the result was clinically significant.
The first case presented chronic disseminated candidiasis, a rare presentation of invasive fungal infection in acute leukemia patients nowadays.4, 5 Despite considering invasive fungal infection the probable diagnosis, it was not confirmed by tissue cultures, and the patient experienced radiological progression despite antifungal therapy. Therefore, the mNGS test was useful for confirming the diagnosis and identifying the Candida species, which allowed antifungal therapy adjustment and patient’s recovery.
In the second case, the mNGS detected an uncommon infection in SCT. Incidence of toxoplasmosis reactivation after SCT is considered rare, depending on the country's prevalence of toxoplasmosis.6 In Brazil, toxoplasmosis seroprevalence is very high, and TMP-SMX prophylaxis is regularly used in the post-SCT period. Despite the absence of tissue documentation, the mNGS contributed to confirm the etiology leading to adequate therapy. Unfortunately, the patient developed a second infection complication, and death occurred within 30 days after toxoplasmosis diagnosis. Mortality rates of toxoplasmosis in SCT patients are reported as 50% or higher by some studies.6, 7
In the last case, mNGS detected disseminated adenoviruses and a recently described virus. Adenovirus can cause a devasting disease in SCT patients. Hemorrhagic cystitis, pneumonia, enteritis, and hepatitis are clinical manifestations of invasive adenovirus, especially after high immunosuppression SCT.8 Torque teno virus (TTV) DNA is commonly found in the plasma of healthy blood donors being considered a non-pathogenic member of the human virome.9 TTV viremia has been evaluated as a surrogate marker of immune function.10
Although mNGS has been applied in several scenarios, some mNGS reports published in leukemia patients showed a contribution considering the broad spectrum of diagnosis possibilities and the consequence of infectious complications in immunocompromised hosts.11, 12
In this study, mNGS obtained from patients with acute leukemia improved the diagnosis of challenging infection diseases and provided the opportunity for adequate therapy.
Ethics approval
This study was approved by the institutional review borders of Hospital 9 de Julho (reference Number: 30907420.1.0000.5455).
Conflicts of interest
The authors declare no conflicts of interest.
Authors contributions
MG, PVO, and MM were involved in the clinical management of patients. LCP, and AC were involved in laboratorial diagnosis. This manuscript was initially drafted by MG, LCP, and AC and then revised by other authors in the study. All authors read and approved the final manuscript.
Acknowledgments
The authors thank R Luz, MR Valentim, J Ramos, JE Levi, for their essential contribution. | DAPTOMYCIN, MEROPENEM | DrugsGivenReaction | CC BY-NC-ND | 33639095 | 19,806,447 | 2021 |
What was the outcome of reaction 'Acute graft versus host disease'? | Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia.
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
pmcIntroduction
Infections remain the most important cause of death in an oncohematological settings, and the spectrum of pathogens is vast and increases concomitantly with immunosuppression.1 Empirical therapies are frequently indicated but with several limitations: overuse of antimicrobials, emergency of antimicrobial resistance, adverse events, and risk of failure. The delay in diagnosis implies a delay in starting appropriate therapy and worse outcomes. Traditional tests based on cultures, biological methods, and serological tests are time-consuming and sometimes are not sufficient to diagnose several infectious complications on hematological patients. Therefore, alternative methodologies are needed for a prompt and correct diagnosis.2, 3
Next-generation metagenomic sequencing (mNGS) has been applied in several scenarios: sepsis, meningitis and encephalitis, bloodstream infection, pneumonia, and others. In these situations, routine microbiologic testing is frequently insufficient to detect uncommon pathogens, making sequencing an attractive approach for the detection of a high number of pathogens in a single platform. This characteristic also contributes to significantly decrease the turnaround time for the result, helping to expedite initiation of an adequate treatment and to have a better outcome.2, 3
Case reports
Case 1
A 38-year-old female with acute myeloid leukemia achieved complete response following induction of remission (cytarabine and daunorubicin) and two consolidations with high dose cytarabine. She developed febrile neutropenia in all chemotherapy cycles without microbiological documentation. Antifungal prophylaxis with fluconazole was given in the first and second cycles. Three months after the last consolidation cycle, she developed fever and malaise. No findings in the clinical exam were noted, and blood cultures were negative. An abdominal CT scan documented solid lesions in the liver. Voriconazole was started to cover chronic disseminated candidiasis, and liver biopsy was performed. In tissue, there was a mixed non-granulomatous inflammatory infiltrate without neoplasia, fungal, or bacterial elements. After two months of voriconazole, symptoms remained, and new solid lesions were noted in the liver and spleen by CT scan. A second liver biopsy was performed, but the culture remained negative. Antifungal was modified empirically to caspofungin, and a sample of blood was collected to perform mNGS (Karius® test). The test was performed by Karius Laboratory (Karius, Redwood City, CA). The standard mNGS protocol is briefly described. During an acute infection, pathogens leave microbial cell-free DNA (cfDNA) in blood. mNGS workflow starts with nucleic acid extraction of the clinical sample, library preparation, and NGS sequencing. Reads are the basic element produced by DNA sequencing. All DNA of a specimen is sequenced in parallel, resulting in isolation and amplification of both host and pathogen nucleic acid sequenced from the sample. The microbial reads were analyzed to identify the composition and abundance of reads of organisms present after removing host DNA from microbial DNA. Results displayed the concentration of pathogen cfDNA detected per microliter of plasma.3 The concentration of each microorganism was compared to the same microorganism's concentration(s) reported in the last 1000 specimens tested by Karius. The mNGS test revealed Candida tropicalis. Caspofungin was maintained, and three months after, symptoms disappeared, and there was a significant reduction in all lesions.
Case 2
A 46-year-old male with a T acute lymphoid leukemia entered a complete remission following induction therapy and received an unrelated allogeneic stem cell transplant (UNR-SCT). Before the transplant, no important infectious event was documented. UNR-SCT conditioning regimen was cyclophosphamide, thymoglobulin, and total body irradiation. During the SCT-neutropenic phase, he developed febrile neutropenia, with negative blood cultures, and was treated empirically with cefepime and vancomycin with a rapid resolution of fever. The patient recovered from neutropenia after 14 days, but a daily fever started after neutrophil recovery. A tiny filamentous in the mitral valve was observed by echocardiography. Empirical therapy with meropenem and daptomycin was started. Concomitantly, acute graft-versus-host disease (GVHD) was noted in the skin and hepatic markers worsened. A few days after, the patient developed acute respiratory failure with a diffuse pulmonary infiltrate by CT scan. Liposomal amphotericin and trimethoprim-sulfamethoxazole (TMP-SMX) were added to therapy. An endemic coronavirus (HKU1) was identified by multiplex-PCR in bronchoalveolar lavage (BAL). Cultures, Galactomannan, Pneumocystis jirovecii-, and tuberculosis-PCR in BAL were negative. At this time, the patient started altering mental status, but the magnetic resonance imaging (MRI) did not reveal any change. A blood sample was collected for mNGS and revealed the presence of Toxoplasma gondii, and TMP-SMX therapy was maintained. New transesophageal echocardiography was performed, and the previous mitral findings were no longer observed. Unfortunately, during toxoplasmosis treatment, the patient developed sepsis due to multiresistant Acinetobacter baumanni in the following days and died. The patient was T. gondii-seropositive (positive IgG and negative IgM) before the transplant.
Case 3
A 34-year-old female with acute lymphoid leukemia in remission received a haploidentical peripheral allogeneic STC (Haplo-SCT) from her brother following conditioning with cyclophosphamide, fludarabine, and total body irradiation. Febrile neutropenia developed during SCT-neutropenic phase, and she was initially treated with empirical cefepime and switched to meropenem and vancomycin due to the persistence of fever despite negative cultures. Neutropenia recovered 16 days after transplantation. On day +18, the patient reported urinary symptoms and gross hematuria. CMV disease was documented (CMV inclusion bodies in bladder tissue and CMV viremia), and ganciclovir was started. Cultures and molecular tests for other viruses (adenovirus, BK, and JC) were negative in urine samples. During ganciclovir therapy, CMV viremia was resolved, but hematuria persisted. Two weeks after, the patient started fever and respiratory symptoms. Nodules, ground-glass infiltrates, and pleural effusion were observed by CT scan. Liposomal amphotericin was started empirically, with a resolution of fever, respiratory symptoms, and radiological improvement. Bronchoalveolar lavage was negative for CMV, galactomannan assay, fungal and bacterial cultures. On D + 60, GVHD was noted in the skin and liver, and corticosteroid was started. Three weeks later, the patient experienced new episodes of fever with moderate to severe respiratory symptoms. A new CT scan showed bilateral infiltrates, centrilobular opacities, and consolidations. Empirical therapies were then restarted, and a sample of blood collected to perform mNGS. Bacterial and fungal cultures, toxoplasmosis, legionella, pneumocystis, and CMV molecular tests were all negative. The mNGS was positive for adenovirus and torque teno virus (TTV). Cidofovir was started, but the patient developed sepsis, renal and respiratory failure, and in a few days, worsened with hemodynamic instability and died.
Discussion
Patients submitted to acute leukemia treatment have considerable risk of infection.1 Although bacterial and fungi etiologies are most frequent, some diagnostically challenging infections occur and require an intensive investigation and a large diagnostical panel. Intense immunosuppression, dense antimicrobial exposure, and emergency of uncommon agents are important factors related to these diagnostically challenging events. In this report, we summarized three patients with acute leukemia in different phases of therapy with complicated, challenging infections. All of them have had their diagnoses based on mNGS (Karius® test) after an intensive laboratory and imaging investigation with no elucidative diagnosis. The Karius® test is a mNGS of microbial cell-free-DNA able to identify and quantify over 1000 clinically relevant pathogens, including bacteria, fungi, parasites, and DNA viruses. It does not cover RNA viruses nor bacterial resistance profiles. Karius reports the concentration of pathogen cfDNA detected per microliter (MPM). As there is no threshold to distinguish colonization from infection, a committee reviewed all results considering MPM, medical history, physical findings, and conventional laboratory tests to confirm if the result was clinically significant.
The first case presented chronic disseminated candidiasis, a rare presentation of invasive fungal infection in acute leukemia patients nowadays.4, 5 Despite considering invasive fungal infection the probable diagnosis, it was not confirmed by tissue cultures, and the patient experienced radiological progression despite antifungal therapy. Therefore, the mNGS test was useful for confirming the diagnosis and identifying the Candida species, which allowed antifungal therapy adjustment and patient’s recovery.
In the second case, the mNGS detected an uncommon infection in SCT. Incidence of toxoplasmosis reactivation after SCT is considered rare, depending on the country's prevalence of toxoplasmosis.6 In Brazil, toxoplasmosis seroprevalence is very high, and TMP-SMX prophylaxis is regularly used in the post-SCT period. Despite the absence of tissue documentation, the mNGS contributed to confirm the etiology leading to adequate therapy. Unfortunately, the patient developed a second infection complication, and death occurred within 30 days after toxoplasmosis diagnosis. Mortality rates of toxoplasmosis in SCT patients are reported as 50% or higher by some studies.6, 7
In the last case, mNGS detected disseminated adenoviruses and a recently described virus. Adenovirus can cause a devasting disease in SCT patients. Hemorrhagic cystitis, pneumonia, enteritis, and hepatitis are clinical manifestations of invasive adenovirus, especially after high immunosuppression SCT.8 Torque teno virus (TTV) DNA is commonly found in the plasma of healthy blood donors being considered a non-pathogenic member of the human virome.9 TTV viremia has been evaluated as a surrogate marker of immune function.10
Although mNGS has been applied in several scenarios, some mNGS reports published in leukemia patients showed a contribution considering the broad spectrum of diagnosis possibilities and the consequence of infectious complications in immunocompromised hosts.11, 12
In this study, mNGS obtained from patients with acute leukemia improved the diagnosis of challenging infection diseases and provided the opportunity for adequate therapy.
Ethics approval
This study was approved by the institutional review borders of Hospital 9 de Julho (reference Number: 30907420.1.0000.5455).
Conflicts of interest
The authors declare no conflicts of interest.
Authors contributions
MG, PVO, and MM were involved in the clinical management of patients. LCP, and AC were involved in laboratorial diagnosis. This manuscript was initially drafted by MG, LCP, and AC and then revised by other authors in the study. All authors read and approved the final manuscript.
Acknowledgments
The authors thank R Luz, MR Valentim, J Ramos, JE Levi, for their essential contribution. | Fatal | ReactionOutcome | CC BY-NC-ND | 33639095 | 19,806,447 | 2021 |
What was the outcome of reaction 'Acute respiratory failure'? | Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia.
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
pmcIntroduction
Infections remain the most important cause of death in an oncohematological settings, and the spectrum of pathogens is vast and increases concomitantly with immunosuppression.1 Empirical therapies are frequently indicated but with several limitations: overuse of antimicrobials, emergency of antimicrobial resistance, adverse events, and risk of failure. The delay in diagnosis implies a delay in starting appropriate therapy and worse outcomes. Traditional tests based on cultures, biological methods, and serological tests are time-consuming and sometimes are not sufficient to diagnose several infectious complications on hematological patients. Therefore, alternative methodologies are needed for a prompt and correct diagnosis.2, 3
Next-generation metagenomic sequencing (mNGS) has been applied in several scenarios: sepsis, meningitis and encephalitis, bloodstream infection, pneumonia, and others. In these situations, routine microbiologic testing is frequently insufficient to detect uncommon pathogens, making sequencing an attractive approach for the detection of a high number of pathogens in a single platform. This characteristic also contributes to significantly decrease the turnaround time for the result, helping to expedite initiation of an adequate treatment and to have a better outcome.2, 3
Case reports
Case 1
A 38-year-old female with acute myeloid leukemia achieved complete response following induction of remission (cytarabine and daunorubicin) and two consolidations with high dose cytarabine. She developed febrile neutropenia in all chemotherapy cycles without microbiological documentation. Antifungal prophylaxis with fluconazole was given in the first and second cycles. Three months after the last consolidation cycle, she developed fever and malaise. No findings in the clinical exam were noted, and blood cultures were negative. An abdominal CT scan documented solid lesions in the liver. Voriconazole was started to cover chronic disseminated candidiasis, and liver biopsy was performed. In tissue, there was a mixed non-granulomatous inflammatory infiltrate without neoplasia, fungal, or bacterial elements. After two months of voriconazole, symptoms remained, and new solid lesions were noted in the liver and spleen by CT scan. A second liver biopsy was performed, but the culture remained negative. Antifungal was modified empirically to caspofungin, and a sample of blood was collected to perform mNGS (Karius® test). The test was performed by Karius Laboratory (Karius, Redwood City, CA). The standard mNGS protocol is briefly described. During an acute infection, pathogens leave microbial cell-free DNA (cfDNA) in blood. mNGS workflow starts with nucleic acid extraction of the clinical sample, library preparation, and NGS sequencing. Reads are the basic element produced by DNA sequencing. All DNA of a specimen is sequenced in parallel, resulting in isolation and amplification of both host and pathogen nucleic acid sequenced from the sample. The microbial reads were analyzed to identify the composition and abundance of reads of organisms present after removing host DNA from microbial DNA. Results displayed the concentration of pathogen cfDNA detected per microliter of plasma.3 The concentration of each microorganism was compared to the same microorganism's concentration(s) reported in the last 1000 specimens tested by Karius. The mNGS test revealed Candida tropicalis. Caspofungin was maintained, and three months after, symptoms disappeared, and there was a significant reduction in all lesions.
Case 2
A 46-year-old male with a T acute lymphoid leukemia entered a complete remission following induction therapy and received an unrelated allogeneic stem cell transplant (UNR-SCT). Before the transplant, no important infectious event was documented. UNR-SCT conditioning regimen was cyclophosphamide, thymoglobulin, and total body irradiation. During the SCT-neutropenic phase, he developed febrile neutropenia, with negative blood cultures, and was treated empirically with cefepime and vancomycin with a rapid resolution of fever. The patient recovered from neutropenia after 14 days, but a daily fever started after neutrophil recovery. A tiny filamentous in the mitral valve was observed by echocardiography. Empirical therapy with meropenem and daptomycin was started. Concomitantly, acute graft-versus-host disease (GVHD) was noted in the skin and hepatic markers worsened. A few days after, the patient developed acute respiratory failure with a diffuse pulmonary infiltrate by CT scan. Liposomal amphotericin and trimethoprim-sulfamethoxazole (TMP-SMX) were added to therapy. An endemic coronavirus (HKU1) was identified by multiplex-PCR in bronchoalveolar lavage (BAL). Cultures, Galactomannan, Pneumocystis jirovecii-, and tuberculosis-PCR in BAL were negative. At this time, the patient started altering mental status, but the magnetic resonance imaging (MRI) did not reveal any change. A blood sample was collected for mNGS and revealed the presence of Toxoplasma gondii, and TMP-SMX therapy was maintained. New transesophageal echocardiography was performed, and the previous mitral findings were no longer observed. Unfortunately, during toxoplasmosis treatment, the patient developed sepsis due to multiresistant Acinetobacter baumanni in the following days and died. The patient was T. gondii-seropositive (positive IgG and negative IgM) before the transplant.
Case 3
A 34-year-old female with acute lymphoid leukemia in remission received a haploidentical peripheral allogeneic STC (Haplo-SCT) from her brother following conditioning with cyclophosphamide, fludarabine, and total body irradiation. Febrile neutropenia developed during SCT-neutropenic phase, and she was initially treated with empirical cefepime and switched to meropenem and vancomycin due to the persistence of fever despite negative cultures. Neutropenia recovered 16 days after transplantation. On day +18, the patient reported urinary symptoms and gross hematuria. CMV disease was documented (CMV inclusion bodies in bladder tissue and CMV viremia), and ganciclovir was started. Cultures and molecular tests for other viruses (adenovirus, BK, and JC) were negative in urine samples. During ganciclovir therapy, CMV viremia was resolved, but hematuria persisted. Two weeks after, the patient started fever and respiratory symptoms. Nodules, ground-glass infiltrates, and pleural effusion were observed by CT scan. Liposomal amphotericin was started empirically, with a resolution of fever, respiratory symptoms, and radiological improvement. Bronchoalveolar lavage was negative for CMV, galactomannan assay, fungal and bacterial cultures. On D + 60, GVHD was noted in the skin and liver, and corticosteroid was started. Three weeks later, the patient experienced new episodes of fever with moderate to severe respiratory symptoms. A new CT scan showed bilateral infiltrates, centrilobular opacities, and consolidations. Empirical therapies were then restarted, and a sample of blood collected to perform mNGS. Bacterial and fungal cultures, toxoplasmosis, legionella, pneumocystis, and CMV molecular tests were all negative. The mNGS was positive for adenovirus and torque teno virus (TTV). Cidofovir was started, but the patient developed sepsis, renal and respiratory failure, and in a few days, worsened with hemodynamic instability and died.
Discussion
Patients submitted to acute leukemia treatment have considerable risk of infection.1 Although bacterial and fungi etiologies are most frequent, some diagnostically challenging infections occur and require an intensive investigation and a large diagnostical panel. Intense immunosuppression, dense antimicrobial exposure, and emergency of uncommon agents are important factors related to these diagnostically challenging events. In this report, we summarized three patients with acute leukemia in different phases of therapy with complicated, challenging infections. All of them have had their diagnoses based on mNGS (Karius® test) after an intensive laboratory and imaging investigation with no elucidative diagnosis. The Karius® test is a mNGS of microbial cell-free-DNA able to identify and quantify over 1000 clinically relevant pathogens, including bacteria, fungi, parasites, and DNA viruses. It does not cover RNA viruses nor bacterial resistance profiles. Karius reports the concentration of pathogen cfDNA detected per microliter (MPM). As there is no threshold to distinguish colonization from infection, a committee reviewed all results considering MPM, medical history, physical findings, and conventional laboratory tests to confirm if the result was clinically significant.
The first case presented chronic disseminated candidiasis, a rare presentation of invasive fungal infection in acute leukemia patients nowadays.4, 5 Despite considering invasive fungal infection the probable diagnosis, it was not confirmed by tissue cultures, and the patient experienced radiological progression despite antifungal therapy. Therefore, the mNGS test was useful for confirming the diagnosis and identifying the Candida species, which allowed antifungal therapy adjustment and patient’s recovery.
In the second case, the mNGS detected an uncommon infection in SCT. Incidence of toxoplasmosis reactivation after SCT is considered rare, depending on the country's prevalence of toxoplasmosis.6 In Brazil, toxoplasmosis seroprevalence is very high, and TMP-SMX prophylaxis is regularly used in the post-SCT period. Despite the absence of tissue documentation, the mNGS contributed to confirm the etiology leading to adequate therapy. Unfortunately, the patient developed a second infection complication, and death occurred within 30 days after toxoplasmosis diagnosis. Mortality rates of toxoplasmosis in SCT patients are reported as 50% or higher by some studies.6, 7
In the last case, mNGS detected disseminated adenoviruses and a recently described virus. Adenovirus can cause a devasting disease in SCT patients. Hemorrhagic cystitis, pneumonia, enteritis, and hepatitis are clinical manifestations of invasive adenovirus, especially after high immunosuppression SCT.8 Torque teno virus (TTV) DNA is commonly found in the plasma of healthy blood donors being considered a non-pathogenic member of the human virome.9 TTV viremia has been evaluated as a surrogate marker of immune function.10
Although mNGS has been applied in several scenarios, some mNGS reports published in leukemia patients showed a contribution considering the broad spectrum of diagnosis possibilities and the consequence of infectious complications in immunocompromised hosts.11, 12
In this study, mNGS obtained from patients with acute leukemia improved the diagnosis of challenging infection diseases and provided the opportunity for adequate therapy.
Ethics approval
This study was approved by the institutional review borders of Hospital 9 de Julho (reference Number: 30907420.1.0000.5455).
Conflicts of interest
The authors declare no conflicts of interest.
Authors contributions
MG, PVO, and MM were involved in the clinical management of patients. LCP, and AC were involved in laboratorial diagnosis. This manuscript was initially drafted by MG, LCP, and AC and then revised by other authors in the study. All authors read and approved the final manuscript.
Acknowledgments
The authors thank R Luz, MR Valentim, J Ramos, JE Levi, for their essential contribution. | Fatal | ReactionOutcome | CC BY-NC-ND | 33639095 | 19,806,447 | 2021 |
What was the outcome of reaction 'Condition aggravated'? | Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia.
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
pmcIntroduction
Infections remain the most important cause of death in an oncohematological settings, and the spectrum of pathogens is vast and increases concomitantly with immunosuppression.1 Empirical therapies are frequently indicated but with several limitations: overuse of antimicrobials, emergency of antimicrobial resistance, adverse events, and risk of failure. The delay in diagnosis implies a delay in starting appropriate therapy and worse outcomes. Traditional tests based on cultures, biological methods, and serological tests are time-consuming and sometimes are not sufficient to diagnose several infectious complications on hematological patients. Therefore, alternative methodologies are needed for a prompt and correct diagnosis.2, 3
Next-generation metagenomic sequencing (mNGS) has been applied in several scenarios: sepsis, meningitis and encephalitis, bloodstream infection, pneumonia, and others. In these situations, routine microbiologic testing is frequently insufficient to detect uncommon pathogens, making sequencing an attractive approach for the detection of a high number of pathogens in a single platform. This characteristic also contributes to significantly decrease the turnaround time for the result, helping to expedite initiation of an adequate treatment and to have a better outcome.2, 3
Case reports
Case 1
A 38-year-old female with acute myeloid leukemia achieved complete response following induction of remission (cytarabine and daunorubicin) and two consolidations with high dose cytarabine. She developed febrile neutropenia in all chemotherapy cycles without microbiological documentation. Antifungal prophylaxis with fluconazole was given in the first and second cycles. Three months after the last consolidation cycle, she developed fever and malaise. No findings in the clinical exam were noted, and blood cultures were negative. An abdominal CT scan documented solid lesions in the liver. Voriconazole was started to cover chronic disseminated candidiasis, and liver biopsy was performed. In tissue, there was a mixed non-granulomatous inflammatory infiltrate without neoplasia, fungal, or bacterial elements. After two months of voriconazole, symptoms remained, and new solid lesions were noted in the liver and spleen by CT scan. A second liver biopsy was performed, but the culture remained negative. Antifungal was modified empirically to caspofungin, and a sample of blood was collected to perform mNGS (Karius® test). The test was performed by Karius Laboratory (Karius, Redwood City, CA). The standard mNGS protocol is briefly described. During an acute infection, pathogens leave microbial cell-free DNA (cfDNA) in blood. mNGS workflow starts with nucleic acid extraction of the clinical sample, library preparation, and NGS sequencing. Reads are the basic element produced by DNA sequencing. All DNA of a specimen is sequenced in parallel, resulting in isolation and amplification of both host and pathogen nucleic acid sequenced from the sample. The microbial reads were analyzed to identify the composition and abundance of reads of organisms present after removing host DNA from microbial DNA. Results displayed the concentration of pathogen cfDNA detected per microliter of plasma.3 The concentration of each microorganism was compared to the same microorganism's concentration(s) reported in the last 1000 specimens tested by Karius. The mNGS test revealed Candida tropicalis. Caspofungin was maintained, and three months after, symptoms disappeared, and there was a significant reduction in all lesions.
Case 2
A 46-year-old male with a T acute lymphoid leukemia entered a complete remission following induction therapy and received an unrelated allogeneic stem cell transplant (UNR-SCT). Before the transplant, no important infectious event was documented. UNR-SCT conditioning regimen was cyclophosphamide, thymoglobulin, and total body irradiation. During the SCT-neutropenic phase, he developed febrile neutropenia, with negative blood cultures, and was treated empirically with cefepime and vancomycin with a rapid resolution of fever. The patient recovered from neutropenia after 14 days, but a daily fever started after neutrophil recovery. A tiny filamentous in the mitral valve was observed by echocardiography. Empirical therapy with meropenem and daptomycin was started. Concomitantly, acute graft-versus-host disease (GVHD) was noted in the skin and hepatic markers worsened. A few days after, the patient developed acute respiratory failure with a diffuse pulmonary infiltrate by CT scan. Liposomal amphotericin and trimethoprim-sulfamethoxazole (TMP-SMX) were added to therapy. An endemic coronavirus (HKU1) was identified by multiplex-PCR in bronchoalveolar lavage (BAL). Cultures, Galactomannan, Pneumocystis jirovecii-, and tuberculosis-PCR in BAL were negative. At this time, the patient started altering mental status, but the magnetic resonance imaging (MRI) did not reveal any change. A blood sample was collected for mNGS and revealed the presence of Toxoplasma gondii, and TMP-SMX therapy was maintained. New transesophageal echocardiography was performed, and the previous mitral findings were no longer observed. Unfortunately, during toxoplasmosis treatment, the patient developed sepsis due to multiresistant Acinetobacter baumanni in the following days and died. The patient was T. gondii-seropositive (positive IgG and negative IgM) before the transplant.
Case 3
A 34-year-old female with acute lymphoid leukemia in remission received a haploidentical peripheral allogeneic STC (Haplo-SCT) from her brother following conditioning with cyclophosphamide, fludarabine, and total body irradiation. Febrile neutropenia developed during SCT-neutropenic phase, and she was initially treated with empirical cefepime and switched to meropenem and vancomycin due to the persistence of fever despite negative cultures. Neutropenia recovered 16 days after transplantation. On day +18, the patient reported urinary symptoms and gross hematuria. CMV disease was documented (CMV inclusion bodies in bladder tissue and CMV viremia), and ganciclovir was started. Cultures and molecular tests for other viruses (adenovirus, BK, and JC) were negative in urine samples. During ganciclovir therapy, CMV viremia was resolved, but hematuria persisted. Two weeks after, the patient started fever and respiratory symptoms. Nodules, ground-glass infiltrates, and pleural effusion were observed by CT scan. Liposomal amphotericin was started empirically, with a resolution of fever, respiratory symptoms, and radiological improvement. Bronchoalveolar lavage was negative for CMV, galactomannan assay, fungal and bacterial cultures. On D + 60, GVHD was noted in the skin and liver, and corticosteroid was started. Three weeks later, the patient experienced new episodes of fever with moderate to severe respiratory symptoms. A new CT scan showed bilateral infiltrates, centrilobular opacities, and consolidations. Empirical therapies were then restarted, and a sample of blood collected to perform mNGS. Bacterial and fungal cultures, toxoplasmosis, legionella, pneumocystis, and CMV molecular tests were all negative. The mNGS was positive for adenovirus and torque teno virus (TTV). Cidofovir was started, but the patient developed sepsis, renal and respiratory failure, and in a few days, worsened with hemodynamic instability and died.
Discussion
Patients submitted to acute leukemia treatment have considerable risk of infection.1 Although bacterial and fungi etiologies are most frequent, some diagnostically challenging infections occur and require an intensive investigation and a large diagnostical panel. Intense immunosuppression, dense antimicrobial exposure, and emergency of uncommon agents are important factors related to these diagnostically challenging events. In this report, we summarized three patients with acute leukemia in different phases of therapy with complicated, challenging infections. All of them have had their diagnoses based on mNGS (Karius® test) after an intensive laboratory and imaging investigation with no elucidative diagnosis. The Karius® test is a mNGS of microbial cell-free-DNA able to identify and quantify over 1000 clinically relevant pathogens, including bacteria, fungi, parasites, and DNA viruses. It does not cover RNA viruses nor bacterial resistance profiles. Karius reports the concentration of pathogen cfDNA detected per microliter (MPM). As there is no threshold to distinguish colonization from infection, a committee reviewed all results considering MPM, medical history, physical findings, and conventional laboratory tests to confirm if the result was clinically significant.
The first case presented chronic disseminated candidiasis, a rare presentation of invasive fungal infection in acute leukemia patients nowadays.4, 5 Despite considering invasive fungal infection the probable diagnosis, it was not confirmed by tissue cultures, and the patient experienced radiological progression despite antifungal therapy. Therefore, the mNGS test was useful for confirming the diagnosis and identifying the Candida species, which allowed antifungal therapy adjustment and patient’s recovery.
In the second case, the mNGS detected an uncommon infection in SCT. Incidence of toxoplasmosis reactivation after SCT is considered rare, depending on the country's prevalence of toxoplasmosis.6 In Brazil, toxoplasmosis seroprevalence is very high, and TMP-SMX prophylaxis is regularly used in the post-SCT period. Despite the absence of tissue documentation, the mNGS contributed to confirm the etiology leading to adequate therapy. Unfortunately, the patient developed a second infection complication, and death occurred within 30 days after toxoplasmosis diagnosis. Mortality rates of toxoplasmosis in SCT patients are reported as 50% or higher by some studies.6, 7
In the last case, mNGS detected disseminated adenoviruses and a recently described virus. Adenovirus can cause a devasting disease in SCT patients. Hemorrhagic cystitis, pneumonia, enteritis, and hepatitis are clinical manifestations of invasive adenovirus, especially after high immunosuppression SCT.8 Torque teno virus (TTV) DNA is commonly found in the plasma of healthy blood donors being considered a non-pathogenic member of the human virome.9 TTV viremia has been evaluated as a surrogate marker of immune function.10
Although mNGS has been applied in several scenarios, some mNGS reports published in leukemia patients showed a contribution considering the broad spectrum of diagnosis possibilities and the consequence of infectious complications in immunocompromised hosts.11, 12
In this study, mNGS obtained from patients with acute leukemia improved the diagnosis of challenging infection diseases and provided the opportunity for adequate therapy.
Ethics approval
This study was approved by the institutional review borders of Hospital 9 de Julho (reference Number: 30907420.1.0000.5455).
Conflicts of interest
The authors declare no conflicts of interest.
Authors contributions
MG, PVO, and MM were involved in the clinical management of patients. LCP, and AC were involved in laboratorial diagnosis. This manuscript was initially drafted by MG, LCP, and AC and then revised by other authors in the study. All authors read and approved the final manuscript.
Acknowledgments
The authors thank R Luz, MR Valentim, J Ramos, JE Levi, for their essential contribution. | Fatal | ReactionOutcome | CC BY-NC-ND | 33639095 | 19,806,447 | 2021 |
What was the outcome of reaction 'Drug ineffective'? | Metagenomic next-generation sequencing (mNGS) for diagnostically challenging infectious diseases in patients with acute leukemia.
This report shows the contribution of next-generation metagenomic sequencing (mNGS) as an alternative to challenging diagnostic infection in immunosuppressed individuals. Herein, we report three acute leukemia patients who developed severe invasive infections due to different etiologies: fungi, viruses, and protozoa. mNGS improved the diagnosis of the infections and provided the opportunity for adequate therapy. The mNGS is a hypothesis-free diagnostic platform, increasing potential in challenging diseases in hematological patients due to the extended diagnostic panel and the expedite access to the result.
pmcIntroduction
Infections remain the most important cause of death in an oncohematological settings, and the spectrum of pathogens is vast and increases concomitantly with immunosuppression.1 Empirical therapies are frequently indicated but with several limitations: overuse of antimicrobials, emergency of antimicrobial resistance, adverse events, and risk of failure. The delay in diagnosis implies a delay in starting appropriate therapy and worse outcomes. Traditional tests based on cultures, biological methods, and serological tests are time-consuming and sometimes are not sufficient to diagnose several infectious complications on hematological patients. Therefore, alternative methodologies are needed for a prompt and correct diagnosis.2, 3
Next-generation metagenomic sequencing (mNGS) has been applied in several scenarios: sepsis, meningitis and encephalitis, bloodstream infection, pneumonia, and others. In these situations, routine microbiologic testing is frequently insufficient to detect uncommon pathogens, making sequencing an attractive approach for the detection of a high number of pathogens in a single platform. This characteristic also contributes to significantly decrease the turnaround time for the result, helping to expedite initiation of an adequate treatment and to have a better outcome.2, 3
Case reports
Case 1
A 38-year-old female with acute myeloid leukemia achieved complete response following induction of remission (cytarabine and daunorubicin) and two consolidations with high dose cytarabine. She developed febrile neutropenia in all chemotherapy cycles without microbiological documentation. Antifungal prophylaxis with fluconazole was given in the first and second cycles. Three months after the last consolidation cycle, she developed fever and malaise. No findings in the clinical exam were noted, and blood cultures were negative. An abdominal CT scan documented solid lesions in the liver. Voriconazole was started to cover chronic disseminated candidiasis, and liver biopsy was performed. In tissue, there was a mixed non-granulomatous inflammatory infiltrate without neoplasia, fungal, or bacterial elements. After two months of voriconazole, symptoms remained, and new solid lesions were noted in the liver and spleen by CT scan. A second liver biopsy was performed, but the culture remained negative. Antifungal was modified empirically to caspofungin, and a sample of blood was collected to perform mNGS (Karius® test). The test was performed by Karius Laboratory (Karius, Redwood City, CA). The standard mNGS protocol is briefly described. During an acute infection, pathogens leave microbial cell-free DNA (cfDNA) in blood. mNGS workflow starts with nucleic acid extraction of the clinical sample, library preparation, and NGS sequencing. Reads are the basic element produced by DNA sequencing. All DNA of a specimen is sequenced in parallel, resulting in isolation and amplification of both host and pathogen nucleic acid sequenced from the sample. The microbial reads were analyzed to identify the composition and abundance of reads of organisms present after removing host DNA from microbial DNA. Results displayed the concentration of pathogen cfDNA detected per microliter of plasma.3 The concentration of each microorganism was compared to the same microorganism's concentration(s) reported in the last 1000 specimens tested by Karius. The mNGS test revealed Candida tropicalis. Caspofungin was maintained, and three months after, symptoms disappeared, and there was a significant reduction in all lesions.
Case 2
A 46-year-old male with a T acute lymphoid leukemia entered a complete remission following induction therapy and received an unrelated allogeneic stem cell transplant (UNR-SCT). Before the transplant, no important infectious event was documented. UNR-SCT conditioning regimen was cyclophosphamide, thymoglobulin, and total body irradiation. During the SCT-neutropenic phase, he developed febrile neutropenia, with negative blood cultures, and was treated empirically with cefepime and vancomycin with a rapid resolution of fever. The patient recovered from neutropenia after 14 days, but a daily fever started after neutrophil recovery. A tiny filamentous in the mitral valve was observed by echocardiography. Empirical therapy with meropenem and daptomycin was started. Concomitantly, acute graft-versus-host disease (GVHD) was noted in the skin and hepatic markers worsened. A few days after, the patient developed acute respiratory failure with a diffuse pulmonary infiltrate by CT scan. Liposomal amphotericin and trimethoprim-sulfamethoxazole (TMP-SMX) were added to therapy. An endemic coronavirus (HKU1) was identified by multiplex-PCR in bronchoalveolar lavage (BAL). Cultures, Galactomannan, Pneumocystis jirovecii-, and tuberculosis-PCR in BAL were negative. At this time, the patient started altering mental status, but the magnetic resonance imaging (MRI) did not reveal any change. A blood sample was collected for mNGS and revealed the presence of Toxoplasma gondii, and TMP-SMX therapy was maintained. New transesophageal echocardiography was performed, and the previous mitral findings were no longer observed. Unfortunately, during toxoplasmosis treatment, the patient developed sepsis due to multiresistant Acinetobacter baumanni in the following days and died. The patient was T. gondii-seropositive (positive IgG and negative IgM) before the transplant.
Case 3
A 34-year-old female with acute lymphoid leukemia in remission received a haploidentical peripheral allogeneic STC (Haplo-SCT) from her brother following conditioning with cyclophosphamide, fludarabine, and total body irradiation. Febrile neutropenia developed during SCT-neutropenic phase, and she was initially treated with empirical cefepime and switched to meropenem and vancomycin due to the persistence of fever despite negative cultures. Neutropenia recovered 16 days after transplantation. On day +18, the patient reported urinary symptoms and gross hematuria. CMV disease was documented (CMV inclusion bodies in bladder tissue and CMV viremia), and ganciclovir was started. Cultures and molecular tests for other viruses (adenovirus, BK, and JC) were negative in urine samples. During ganciclovir therapy, CMV viremia was resolved, but hematuria persisted. Two weeks after, the patient started fever and respiratory symptoms. Nodules, ground-glass infiltrates, and pleural effusion were observed by CT scan. Liposomal amphotericin was started empirically, with a resolution of fever, respiratory symptoms, and radiological improvement. Bronchoalveolar lavage was negative for CMV, galactomannan assay, fungal and bacterial cultures. On D + 60, GVHD was noted in the skin and liver, and corticosteroid was started. Three weeks later, the patient experienced new episodes of fever with moderate to severe respiratory symptoms. A new CT scan showed bilateral infiltrates, centrilobular opacities, and consolidations. Empirical therapies were then restarted, and a sample of blood collected to perform mNGS. Bacterial and fungal cultures, toxoplasmosis, legionella, pneumocystis, and CMV molecular tests were all negative. The mNGS was positive for adenovirus and torque teno virus (TTV). Cidofovir was started, but the patient developed sepsis, renal and respiratory failure, and in a few days, worsened with hemodynamic instability and died.
Discussion
Patients submitted to acute leukemia treatment have considerable risk of infection.1 Although bacterial and fungi etiologies are most frequent, some diagnostically challenging infections occur and require an intensive investigation and a large diagnostical panel. Intense immunosuppression, dense antimicrobial exposure, and emergency of uncommon agents are important factors related to these diagnostically challenging events. In this report, we summarized three patients with acute leukemia in different phases of therapy with complicated, challenging infections. All of them have had their diagnoses based on mNGS (Karius® test) after an intensive laboratory and imaging investigation with no elucidative diagnosis. The Karius® test is a mNGS of microbial cell-free-DNA able to identify and quantify over 1000 clinically relevant pathogens, including bacteria, fungi, parasites, and DNA viruses. It does not cover RNA viruses nor bacterial resistance profiles. Karius reports the concentration of pathogen cfDNA detected per microliter (MPM). As there is no threshold to distinguish colonization from infection, a committee reviewed all results considering MPM, medical history, physical findings, and conventional laboratory tests to confirm if the result was clinically significant.
The first case presented chronic disseminated candidiasis, a rare presentation of invasive fungal infection in acute leukemia patients nowadays.4, 5 Despite considering invasive fungal infection the probable diagnosis, it was not confirmed by tissue cultures, and the patient experienced radiological progression despite antifungal therapy. Therefore, the mNGS test was useful for confirming the diagnosis and identifying the Candida species, which allowed antifungal therapy adjustment and patient’s recovery.
In the second case, the mNGS detected an uncommon infection in SCT. Incidence of toxoplasmosis reactivation after SCT is considered rare, depending on the country's prevalence of toxoplasmosis.6 In Brazil, toxoplasmosis seroprevalence is very high, and TMP-SMX prophylaxis is regularly used in the post-SCT period. Despite the absence of tissue documentation, the mNGS contributed to confirm the etiology leading to adequate therapy. Unfortunately, the patient developed a second infection complication, and death occurred within 30 days after toxoplasmosis diagnosis. Mortality rates of toxoplasmosis in SCT patients are reported as 50% or higher by some studies.6, 7
In the last case, mNGS detected disseminated adenoviruses and a recently described virus. Adenovirus can cause a devasting disease in SCT patients. Hemorrhagic cystitis, pneumonia, enteritis, and hepatitis are clinical manifestations of invasive adenovirus, especially after high immunosuppression SCT.8 Torque teno virus (TTV) DNA is commonly found in the plasma of healthy blood donors being considered a non-pathogenic member of the human virome.9 TTV viremia has been evaluated as a surrogate marker of immune function.10
Although mNGS has been applied in several scenarios, some mNGS reports published in leukemia patients showed a contribution considering the broad spectrum of diagnosis possibilities and the consequence of infectious complications in immunocompromised hosts.11, 12
In this study, mNGS obtained from patients with acute leukemia improved the diagnosis of challenging infection diseases and provided the opportunity for adequate therapy.
Ethics approval
This study was approved by the institutional review borders of Hospital 9 de Julho (reference Number: 30907420.1.0000.5455).
Conflicts of interest
The authors declare no conflicts of interest.
Authors contributions
MG, PVO, and MM were involved in the clinical management of patients. LCP, and AC were involved in laboratorial diagnosis. This manuscript was initially drafted by MG, LCP, and AC and then revised by other authors in the study. All authors read and approved the final manuscript.
Acknowledgments
The authors thank R Luz, MR Valentim, J Ramos, JE Levi, for their essential contribution. | Fatal | ReactionOutcome | CC BY-NC-ND | 33639095 | 19,806,447 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea exertional'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Enzyme abnormality'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,871,519 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gait disturbance'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypophagia'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Memory impairment'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Muscle atrophy'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Muscular weakness'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,058,835 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,058,835 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tachycardia'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Weight decreased'. | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | FLUOXETINE HYDROCHLORIDE, HYDROCHLOROTHIAZIDE, LIOTHYRONINE SODIUM, METFORMIN HYDROCHLORIDE, OXAZOLAM, PSEUDOEPHEDRINE HYDROCHLORIDE, TOPIRAMATE | DrugsGivenReaction | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the administration route of drug 'METFORMIN HYDROCHLORIDE'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33639866 | 19,025,448 | 2021-02-27 |
What was the administration route of drug 'TOPIRAMATE'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33639866 | 19,025,448 | 2021-02-27 |
What was the dosage of drug 'FLUOXETINE HYDROCHLORIDE'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the dosage of drug 'HYDROCHLOROTHIAZIDE'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the dosage of drug 'LIOTHYRONINE SODIUM'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the dosage of drug 'METFORMIN HYDROCHLORIDE'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the dosage of drug 'OXAZOLAM'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the dosage of drug 'PSEUDOEPHEDRINE HYDROCHLORIDE'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the dosage of drug 'TOPIRAMATE'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Decreased appetite'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Dyspnoea exertional'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Enzyme abnormality'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,871,519 | 2021-02-27 |
What was the outcome of reaction 'Gait disturbance'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Hypophagia'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Memory impairment'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Muscle atrophy'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Muscular weakness'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Myopathy'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,025,448 | 2021-02-27 |
What was the outcome of reaction 'Tachycardia'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
What was the outcome of reaction 'Weight decreased'? | Exacerbation of myopathy triggered by antiobesity drugs in a patient with multiple acyl-CoA dehydrogenase deficiency.
BACKGROUND
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a treatable lipid metabolism disorder that presents as myopathy and episodic metabolic crisis. The metabolic crisis is typically associated with prolonged fasting or physical stress; however, the mechanism of metabolic crisis is not yet fully understood.
METHODS
A 28-year-old Taiwanese woman presented with dyspnoea, poor appetite, and muscle weakness after using antiobesity drugs, including metformin, triiodothyronine, and topiramate. MADD was diagnosed, and her symptoms rapidly improved after treatment with riboflavin, carnitine, and ubiquinone. To date, antiobesity drugs have not been reported to be a provoking factor in fatty acid oxidation disorder.
CONCLUSIONS
The increase of β-oxidation activity due to antiobesity drugs supports the hypothetical substrate competition model for MADD metabolic crisis. Because the drugs our patient used are commonly prescribed, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable adult-onset myopathy.
Background
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a lipid metabolism disorder caused by defects in electron transfer flavoprotein or electron transfer protein dehydrogenase, encoded by ETFA, ETFB, and ETFDH. MADD is the most prevalent lipid storage disease in Taiwan, where the hotspot mutation ETFDH c.250G > A has a carrier frequency of 0.8% [1]. Patients with late-onset MADD typically present with lipid storage myopathy and episodic metabolic crisis. Metabolic crisis is usually associated with prolonged fasting or physical stress and manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. The mechanism of metabolic crisis is not yet fully understood. Herein, we report the case of a patient with late-onset MADD who had an episodic exacerbation of muscle weakness after taking antiobesity drugs. This provoking factor has yet to be addressed in the literature. All possible mechanisms were reviewed and discussed. This report was approved by the Institutional Review Board of National Cheng Kung University Hospital (IRB Approval No. A-EC-108-009).
Case presentation
The 28-year-old Taiwanese woman whose condition is reported herein had an uneventful birth and developmental history. She exhibited suboptimal performance in exercise since elementary school age, especially in long-distance running. She experienced one episode of reversible proximal limb weakness for 3 days when she was 21 years old. She denied any weakness at baseline. She used antiobesity drugs, and in the preceding 4 months, her body weight decreased from 60 to 47 kg, with a corresponding reduction in body mass index from 22.3 to 17.5. The regimen of antiobesity drugs included metformin, triiodothyronine, topiramate, pseudoephedrine, hydrochlorothiazide, fluoxetine, and oxazolam. She was not prescribed diet change or caloric restriction. After weight loss, she exhibited poor appetite; poor oral intake; dyspnoea on exertion; and progressive weakness and soreness in the four proximal limbs, the neck, and the trunk. She was aided by a wheelchair upon admission.
On examination, the patient had intermittent tachycardia and dyspnoea on minimal exertion but had otherwise normal vital signs. She had reduced muscle strength in the proximal limbs (manual muscle power: bilateral deltoid: 3; bilateral finger abduction: 5; bilateral hip flexion: 4; bilateral dorsiflexion: 5), neck, and trunk, with positive Gowers’ sign and myopathic gait. Generalised muscle wasting involving the neck, trunk, shoulder girdle, pelvic girdle, and proximal and distal limbs but not the facial muscles was observed (Fig. 1a-c). No percussion myotonia was noted. The patient had mildly decreased memory and calculation abilities compared with healthy individuals of an equivalent age. Examinations for cranial nerve, deep tendon reflex, sensory, and coordination function revealed unremarkable results. She had no hepatosplenomegaly, goitre, or skin hyperpigmentation.
Fig. 1 Clinical information. The patient exhibited prominent atrophy in the muscles of the neck (a, white arrow), shoulder girdle (a, black arrow), bilateral first dorsal interosseous muscles (b, white arrows), bilateral legs (c, black arrow), and feet (c, white arrow). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (d, X axis, serum acylcarnitine with various chain lengths. Y axis, ratio of the serum acylcarnitine level of this patient and the upper limit of the normal range in those of equivalent age)
Laboratory exams indicated elevated serum creatinine kinase (496 U/L), elevated aspartate aminotransferase (102 U/L), elevated resting serum lactate (4.7 mmol/L), and borderline elevated serum calcium (10.2 mg/dL) levels. Blood count, estimated glomerular filtration rate, serum electrolyte levels (including sodium, potassium, and magnesium), and thyroid function were unremarkable. An arterial blood gas test revealed no hypoxemia, hypercapnia, or acid–base problems. A nerve conduction study yielded no evidence of polyneuropathy. Electromyography demonstrated myopathic motor unit action potential with early recruitment pattern as well as no spontaneous activity in all sampled muscles in the four proximal and distal limbs. An aerobic forearm exercise test [2] revealed elevated mixed venous oxygen saturation after 3 min of aerobic exercise, suggesting defective oxidative metabolism in the muscles (Table 1). Muscle magnetic resonance imaging of the bilateral thighs was unremarkable. Muscle pathology of the right rectus femoris muscle suggested lipid storage myopathy (Fig. 2). Tandem mass spectrometry of serum acylcarnitine revealed elevated short-, medium-, and long-chain acylcarnitines with secondary carnitine deficiency (Fig. 1d). Urine organic acid analysis indicated glutaric aciduria. ETFDH gene analysis revealed compound heterozygous mutations c.250G > A / p.Ala84Thr and c.524G > T / p.Arg175Leu. Both variants have previously been reported to be pathogenic [1, 3]. MADD was therefore diagnosed. We treated the patient with riboflavin, carnitine, and ubiquinone, and her symptoms rapidly improved. She was able to walk without assistance within 2 weeks, and she became asymptomatic within 3 months.
Table 1 Aerobic forearm exercise test. PvO2, lactate, pyruvate, and lactate/pyruvate ratios before and after exercise
PvO2a (mmHg) Lactate (mmol/L) Pyruvate (μmol/L) Lactate/pyruvate
Pre-exercise 46 2.1 116 18.1
Post-exercise 0 min 62 5.1 118 43.2
Post-exercise 8 min 52 2.6 132 19.7
aPvO2 mixed venous oxygen saturation
Fig. 2 Muscle pathology. The haematoxylin and eosin slide indicated mildly varied muscle fibre size and scattered small vacuoles (a). The ATPase stain (pH 4.6) demonstrated that the vacuoles were mainly in type 1 fibres (b, dark colour fibres). The modified Gomori trichrome stain showed no ragged red fibres (c). The oil red O stain revealed increased lipid droplets in size and number in scattered fibres (d, tiny red droplets). Transmission electron microscopy indicated increased lipid droplet and mitochondria counts (e), with abnormal cristae and some dense inclusion in mitochondria (e inset). (Scale bar, 100 μm in B1–B4 and 500 nm in B5)
Discussion and conclusions
MADD is a lipid metabolism disorder that is caused by defects in electron transfer flavoprotein, which is encoded by ETFA and ETFB, or defects in electron transfer flavoprotein dehydrogenase, encoded by the ETFDH. Electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase are located on the matrix face of the inner mitochondrial membrane and are involved in the oxidation of fatty acids. The aforementioned defects disturb electron transfer from acyl-CoA dehydrogenase (ACAD) through flavoproteins to ubiquinone and finally result in an accumulation of acyl-CoA of various chain lengths.
Late-onset MADD typically presents as lipid storage myopathy and episodic metabolic crisis. The myopathy usually manifests as proximal muscle weakness. Cardiomyopathy and respiratory insufficiency have also been reported. Metabolic crisis typically manifests as the exacerbation of weakness, lethargy, vomiting, hypoketotic hypoglycaemia, and metabolic acidosis. Common precipitating factors of acute exacerbation include prolonged fasting or physical stress such as exercise or infection [4]. To date, antiobesity drugs have not been reported as a provoking factor. Regarding the possible mechanisms by which the drugs induced metabolic crisis, this report supports the hypothetical model of substrate competition in disorders involving β-oxidation dysfunction. In the substrate competition model of fatty acid oxidation, the accumulation of acyl-CoA of a certain chain length acts as competitive inhibitor of ACADs of different chain lengths [5]. Therefore, the accumulation of acyl-CoA with multiple chain lengths exacerbates the dysfunction of multiple ACADs and forms the basis of metabolic crisis [6]. Moreover, coenzyme A may be trapped as acyl-CoA and lead to dysfunction of glucose metabolism, which results in profound energy failure [7]. Chokchaiwong et al. studied the mitochondrial bioenergetics of cells with ETFDH mutation and observed reduced mitochondrial membrane potential upon fatty acid challenge, supporting the concept of substrate competition in vitro; these researchers also reported decreased mRNA and protein levels of ETFDH upon fatty acid challenge, suggesting a complex negative feedback loop governing the pathophysiology of metabolic crisis [8].
Antiobesity drugs accelerate lipid catabolism. Microcosmically, they act comparably to a fatty acid challenge towards mitochondria, as in the aforementioned in vitro cell model. Metformin, one of our patient’s antiobesity drugs, is an electron transport chain complex I inhibitor, which activates AMP-activated protein kinase (AMPK) by increasing the AMP:ATP ratio. The AMPK pathway accelerates fatty acid transportation into mitochondria, which is typically the rate-limiting step of fatty acid oxidation [9]. Thyroid hormone directly enhances lipid oxidation by increasing AMPK pathway activity, carnitine palmitoyl transferase activity, flavin adenine dinucleotide-linked respiratory pathway activity, and mitochondrial trifunctional protein activity [10]. Topiramate increases fatty acid oxidation by increasing lipoprotein lipase activity and adiponectin levels and thus AMPK pathway activity [11]. Taken together, the results indicate that the acute exacerbation of muscle strength after antiobesity drug use likely resulted from an overload of fatty acid oxidation at multiple steps in a suboptimal lipid metabolism system. This supports the notion of substrate competition.
This case report has two main strengths. First, this is the first reported case of a patient with MADD who had in vivo lipid challenge induced by medication, which supports the substrate competition model. Second, the diagnosis in this case was comprehensively confirmed through genetic and metabolic diagnosis, and complete improvement after treatment was verified. Nevertheless, this report has two limitations. First, the patient used multiple antiobesity drugs simultaneously; thus, inferring which drug contributed most to the exacerbation is challenging. Second, reproducing the exacerbation episode was infeasible for ethical reasons.
The medications this patient used, including metformin, thyroid hormone, and topiramate, are commonly used in clinical practice and can affect lipid metabolism, resulting in acute decompensation in patients with MADD. Thus, we report this case to increase the vigilance and proactivity of clinicians in recognising this treatable form of adult-onset myopathy.
Abbreviations
MADDMultiple acyl-CoA dehydrogenase deficiency
ACADAcyl-CoA dehydrogenase
AMPKAMP-activated protein kinase
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Professor Chou-Ching Lin for providing assistance in caring for the patient.
Authors’ contributions
PYL, WCL, and YTS obtained, analysed and interpreted the clinical data. WCL and WAL obtained, analysed, and interpreted the pathologic data. PYL drafted the manuscript. WCL, WAL, and YTS revised the manuscript critically for critical intellectual content. All authors have read and approved the manuscript for publication.
Funding
No targeted funding is reported.
Availability of data and materials
Data sharing is not applicable to this article because no datasets were generated or analysed in the current study.
Declarations
Ethics approval and consent to participate
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009).
Consent for publication
The manuscript was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital for publication (IRB Approval No. A-EC-108-009). Written informed consent was obtained from the patient.
Competing interests
The authors declare no competing interests. | Recovered | ReactionOutcome | CC BY | 33639866 | 19,084,520 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral infarction'. | An unusual case of Cardiobacterium valvarum causing aortic endograft infection and osteomyelitis.
BACKGROUND
HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.) group organisms are responsible for 0.8% to 6% of all infective endocarditis cases, with Cardiobacterium spp. being the third most commonly implicated HACEK microorganism. Within this genus is Cardiobacterium valvarum (C. valvarum), a novel organism described in 2004. To date, only 15 cases of C. valvarum infection have been reported in the English-language literature, and have primarily been cases of infective endocarditis in patients with valvular disease. C. valvarum has not been reported to cause infections spreading to the surrounding bone.
METHODS
We present a case of a 57-year-old man with a history of aortic dissection followed by aortic endograft replacement who presented with back pain. He was found to have radiographic evidence of an infected aortic endograft, along with vertebral osteomyelitis, discitis, and epidural phlegmon. Blood cultures identified C. valvarum as the causative organism. The patient was treated with ceftriaxone and surgical intervention was deferred due to the patient's complex anatomy. His course was complicated by septic cerebral emboli resulting in cerebrovascular accident.
CONCLUSIONS
This case report highlights C. valvarum, a rare and emerging HACEK group microorganism that warrants consideration in high-risk patients with evidence of subacute infection and disseminated disease. While C. valvarum classically presents as infective endocarditis, extra-cardiac manifestations have also been described. As demonstrated in this case, endograft involvement and osteomyelitis may occur in rare circumstances.
Background
Cardiobacterium spp. are fastidious, pleomorphic Gram-negative bacilli that belong to the HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.) group of microorganisms, a group of bacteria that share similar microbiological and clinical characteristics. Species within this group have been reported to be responsible for 0.8–6.0% of all infective endocarditis cases [1]. Although an uncommon cause of endocarditis overall, Cardiobacterium spp. are the third most common HACEK microorganism implicated in HACEK endocarditis [1]. Few reports of extra-cardiac Cardiobacterium spp. infection have been described [2, 3], and there are no known reports of the C. valvarum species being implicated in osteomyelitis.
Herein, we report a case of C. valvarum aortic endograft infection, which was further complicated by vertebral discitis, epidural phlegmon, septic cerebral emboli, and the first known case of C. valvarum osteomyelitis. A review of the English-language literature follows the case presentation.
Case presentation
In June 2020, a 57-year-old man was directly admitted to the hospital for radiologic evidence of vertebral osteomyelitis, discitis, and epidural phlegmon. He had a history of hypertension, hyperlipidemia, prediabetes, chronic kidney disease, and an acute Stanford Type A and Type B aortic dissection. His Type A aortic dissection (defined as involvement of the ascending aorta) had led to an emergent resection and replacement of the ascending aorta and proximal arch with a Dacron endograft nine years prior to his current presentation. Subsequent progression of an associated aortic arch aneurysm required surgical revision with a Dacron endograft exchange five years after initial surgical repair. His Type B dissection (defined as being limited to the aorta distal to the left subclavian artery without involvement of the ascending aorta) extended from the proximal aortic arch to the aortic bifurcation and remained untreated, though partially thrombosed. He had no other recent surgical instrumentation and his last dental procedure was ~ 24 months prior to his current presentation. Medications included amlodipine, aspirin, atorvastatin, carvedilol, ezetimibe, and lisinopril. He used alcohol socially and had never used tobacco or illicit drugs.
The patient had been well until ~ 6 weeks prior when isolated lower back pain developed. At that time, an outpatient non-contrast-enhanced magnetic resonance imaging (MRI) of the lumbar spine demonstrated significant edema within the vertebral bodies adjacent to the L4–L5 intervertebral disc space. Given his absence of systemic symptoms, short-term follow-up was advised. Two weeks later, a repeat contrast-enhanced MRI of the lumbar spine demonstrated progressive T2 hyperintensity at the L4–L5 intervertebral disc space and adjacent endplates with near complete involvement of the L3 and L4 vertebral bodies, highly suggestive of vertebral osteomyelitis and discitis (Fig. 1a). In addition, there was a 6 mm thick anterior epidural thickening and enhancement suggestive of epidural phlegmon that extended to L3 superiorly, S1 inferiorly, and the posterior wall of the known abdominal aortic aneurysm anteriorly (Fig. 1b). He was admitted for further workup and management.Fig. 1 Magnetic resonance imaging (MRI) of the lumbar spine demonstrating discitis and vertebral osteomyelitis. T1 post-contrast sagittal MRI demonstrating enhancement at the L3–4 intervertebral disc space with erosions in the adjacent endplates (arrow)
On admission, a temperature of 37.2 °C, heart rate of 74 beats per min, blood pressure of 129/67 mm Hg, and body-mass index of 32.7 were observed. On examination, there were multiple dental amalgam fillings and a 3/6 systolic murmur best appreciated in the aortic region, which was stable from prior. The remainder of the examination, including a focused neurologic, musculoskeletal, and dermatologic assessment, was normal. Basic laboratory tests were remarkable for anemia of inflammation, a C-reactive protein of 1.6 mg/dL (reference range, 0.0–0.5 mg/dL), an erythrocyte sedimentation rate of 53 mm/h (reference range, 3–10 mm/h), and the absence of leukocytosis. Aerobic and anaerobic peripheral blood cultures were obtained, and empiric vancomycin 1 g intravenously every 12 h and cefepime 2 g intravenously every 12 h were administered due to the proximity of the epidural phlegmon to the posterior wall of the known abdominal aortic aneurysm.
A series of diagnostic tests were subsequently performed. Computed tomography (CT) angiography of the thoracic aorta showed a soft tissue density located on the ascending aortic endograft, favored to be infectious in etiology. Transesophageal echocardiogram showed previously noted strand-like mobile echodensities on the right coronary cusp of the aortic valve, favored to represent Lambl’s excrescences (defined as thin, fibrinous structures at the lines of valve closure and postulated to be related to shear forces to the endothelium) [4]. There were no other valvular abnormalities or signs of valvular insufficiency. Contrast-enhanced CT of the face showed no evidence of dental disease. Fluoroscopy-guided bone biopsy of the L4 vertebral body obtained on day 3 of admission showed changes suggestive of resolving osteomyelitis. On day 4 of admission, 2 of 2 bottles on both sets of initial peripheral blood cultures signaled positive at 96 h of incubation. Macroscopically, colonies were described as irregular, small, round, and opaque in color. Nevertheless, due to poor growth secondary to the fastidious nature of the organism, susceptibilities were unable to be performed. Bipolar-staining pleomorphic Gram-negative rod-shaped bacilli were seen on microscopy (Fig. 2). 16S ribosomal RNA sequencing analysis subsequently identified C. valvarum (see Appendix 1 for further information regarding methods). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for further identification was not performed. Aerobic and anaerobic vertebral biopsy cultures remained negative and 16S ribosomal RNA sequencing was unfortunately not performed on these specimens. Though not definitively documented in the bone, C. valvarum identified in the blood was presumed to be the cause of the focal lesion as well.Fig. 2 Gram staining. Microscopic morphology in gram staining of blood culture after 96 h of aerobic incubation at 37 °C demonstrating bipolar-staining gram-negative bacilli. 16S ribosomal RNA (rRNA) sequencing subsequently identified the organism as Cardiobacterium valvarum
Antimicrobial therapy was changed to ceftriaxone 2 g intravenously daily and prescribed for a 6-week course. Given radiologic evidence of a possible aortic endograft nidus, a vascular surgery evaluation was obtained. Surgical intervention was ultimately deferred due to the high likelihood of extensive endograft involvement and the technical difficulty posed by the patient’s complex surgical history. The patient was discharged home on day 9 of admission with multidisciplinary follow-up and outpatient antimicrobial therapy.
Twenty days later, the patient was readmitted for acute headache and blurry vision in the left eye. MRI of the brain at that time showed a moderate-sized acute and subacute right posterior cerebral artery (PCA) territory infarct of the right occipital and posterior temporal lobes with a small focus of associated hemorrhagic transformation. Magnetic resonance angiography of the brain subsequently showed poor flow-related signal of the right PCA P3/P4 segment with a paucity of vessels in the right occipital lobe suspicious for occlusion. Monitoring of the bilateral PCAs with a 2-MHz transcranial doppler ultrasound showed nine microembolic signals within the right PCA, suspicious for septic emboli. No neurosurgical intervention was pursued, initial antithrombotic therapy was held, and repeat peripheral blood cultures were negative. Positron emission tomography–computed tomography (PET/CT) was then obtained to better characterize the aortic endograft, which showed hypermetabolic soft tissue along the right lateral and anterior aspect of the ascending aortic graft, once again suspicious for endograft infection (Fig. 3). Surgical intervention was again deferred, and the patient was discharged home on hospital day 7. He was continued on ceftriaxone 2 g intravenously daily with the addition of clopidogrel 75 mg daily and levetiracetam 1 g twice daily. He remains well in multidisciplinary outpatient follow-up with marked improvement in his back pain and no further complication. He will remain on lifelong suppressive antimicrobial therapy following his initial treatment course.Fig. 3 Positron emission tomography–computed tomography (PET/CT) of the chest. Hypermetabolic soft tissue (arrows) along the right lateral and anterior aspect of the ascending aortic endograft with a maximum standardized uptake value of 9.4, suspicious for aortic endograft infection
Discussion
The Cardiobacterium genus was first described in 1964 when its major and prior sole species, C. hominis, was recognized as a distinct microorganism by Slotnick and Dougherty [5]. C. hominis itself is a low-virulence, commensal and facultative Gram-negative bacillus that typically manifests in patients with subacute endocarditis. Historically, its microbiologic detection has been challenging due to its fastidious nature and slow-growth on traditional media.
In 2004, a novel Cardiobacterium species designated C. valvarum was isolated from the blood of a 37-year-old man with subacute endocarditis of a congenital bicuspid aortic valve and sudden rupture of a cerebral aneurysm [6]. In comparison to the major C. hominis species, C. valvarum grows more slowly, is non-hemolytic on sheep blood agar, and does not utilize sucrose, maltose, or mannitol on traditional media [6]. Since its initial recognition, there have been 15 total cases of C. valvarum infection reported in the English-language literature, all of which have utilized 16S ribosomal RNA sequencing as a means of detection [6–23]. Table 1 provides an overview of these cases. In the overwhelming majority, clinical presentations are insidious and without apparent signs of a systemic inflammatory response, such as pyrexia or chills [6, 7, 12–16]. Factors that appear to predispose patients to infection with C. valvarum include recent dental instrumentation [6, 10, 15, 16], poor dentition [9, 15, 18], and congenital cardiac disease [6, 8–10, 12, 13, 15–17, 19]. Importantly, the presence of a congenital bicuspid aortic valve appears to be strongly associated with C. valvarum pathogenicity [6, 8, 9, 13, 16, 19]. Common imaging findings in infected hosts typically include large (> 1 cm) valvular vegetations on echocardiography [6–9, 12, 16, 18, 20], and, in settings where acute neurologic dysfunction is evident, septic cerebral emboli resulting in cerebrovascular accident [6–8, 12–14, 18].Table 1 Existing case reports documenting infection by Cardiobacterium valvarum
Han et al. (2004) Hoover et al. (2005) Bothelo et al. (2006) Gonzalez et al. (2007) Geissdorfer et al. (2007) Vaněrková et al. (2010) Hoffman et al. (2010) Chen et al. (2011) Abraham et al. (2012) Choudhury et al. (2013) Pusch et al. (2015) Bonavent et al. (2016) Ni et al. (2018) Irabien et al. (2019)
Patient age 37 46 51 29 71 63 28 64 65 53 45 72 41 18
Symptoms at presentation Insidious, cardiopulmonary Insidious Insidious Insidious Insidious Insidious Insidious, cardiopulmonary Insidious Insidious, cardiopulmonary Insidious Cardiopulmonary Neurologic Cardiopulmonary Insidious
Risk factors Dental Dental, cardiac Dental, cardiac None Cardiac None Dental, cardiac Dental, cardiac None Dental, cardiac Cardiac Cardiac Dental Cardiac
Cardiac imaging findings Valvular disease, vegetations Valvular disease, reduced LVEF Vegetations,
Abscess
Valvular disease, aortic dehiscence Valvular disease, vegetations, abscess Valvular disease, vegetations Valvular disease, vegetation Valvular disease Valvular disease, vegetations Valvular disease Vegetations Valvular disease, vegetations Valvular disease, vegetations Valvular disease
Neurologic symptoms Facial Droop None None Slurred speech, numbness Weakness None None None Dysphasia, hemiplegia, facial weakness, Babinski’s sign Headache None Vision loss, confusion None None
CNS imaging findings SAH None None Acute infarcts Acute infarcts None None None vasculitis, acute infarct Acute infarcts None Acute infarct SAH, acute infarct None
Surgical intervention AVR AVR AVR AVR AVR AVR, TVA Replacement
Prosthetic
Valve-conduit
MVR None AVR None AVR MVR, TVA Repair MV, TV, ASD, RVOT Conduit
Antimicrobial
treatment
Piperacillin-tazobactam Ceftriaxone Amoxicillin,
gentamicin
Ceftriaxone,
vancomycin
Ceftriaxone,
rifampin, amikacin
Ceftriaxone,
gentamicin, cefuroxime
Ceftriaxone Cefuroxime,
gentamicin
Gentamicin, piperacillin-tazobactam Ceftriaxone, levofloxacin Ceftriaxone Penicillin, gentamicin, moxifloxacin Ceftizoxime Ceftriaxone
Clinical outcome Alive Alive Unknown Alive Deceased Alive Alive Alive Deceased Alive Alive Alive Alive Alive
CNS indicates central nervous system, LVEF left ventricular ejection fraction, SAH subarachnoid hemorrhage, AVR aortic valve replacement, MVR mitral valve replacement, TVA tricuspid valve annuloplasty, MV mitral valve, TV tricuspid valve, ASD atrial septal defect, RVOT right ventricular outflow tract
In the present case, C. valvarum bacteremia was suspected to have caused an endograft infection, later spreading to the bone. The presumed source of C. valvarum was the oral cavity given that the patient had undergone at least one dental procedure in the interim between his aortic arch surgical revision and the onset of lower back pain. While it is unclear if the patient was ever prescribed prophylactic antibiotic therapy prior to any known dental procedure, one possibility is that transient bacteremia resulting from one of these procedures seeded the aortic Dacron endograft. Transient bacteremia may also have resulted from manipulation associated with toothbrushing. The endograft may have then served as a nidus for recurrent episodes of transient bacteremia, leading to lumbar spine infection with subsequent development of osteomyelitis and contiguous spread into the epidural and intervertebral disc spaces. It should be noted that a single report of C. valvarum aortic endograft infection confirmed by 16S ribosomal RNA sequence analysis has been previously described in a 53-year-old man with total aortic arch replacement and severe aortic regurgitation in Japan [14]. Likewise, a Cardiobacterium spp (C. hominis) causing vertebral osteomyelitis, discitis, and epidural abscess has also been described [21]. To our knowledge, the present case describes the first known case of C. valvarum both affecting an aortic endograft and resulting in osteomyelitis. It should be noted that, in our case, vertebral bone biopsy cultures did not grow any organisms, although the C. valvarum identified in the blood was presumed to be the cause of the osteomyelitis as well.
In any patient with confirmed Cardiobacterium spp. infection, careful evaluation for the presence of infective endocarditis is mandatory given the high likelihood of cardiac involvement. In contrast to the majority of cases shown in Table 1 that met modified Duke criteria for “Definite” infective endocarditis, the present case was designated as “Possible” infective endocarditis by only meeting one major clinical criterion (blood cultures with a typical infective endocarditis microorganism) and two minor clinical criteria (predisposing cardiac condition and vascular phenomena) [22]. Notably, there was no echocardiographic evidence of endocardial or valvular involvement on both transthoracic and transesophageal studies. While mobile strand-like echodensities were noted on aortic valve imaging, these were favored to represent Lambl’s excrescences [4] and had been noted on previous echocardiographic examinations that predated his aortic dissection. Therefore, though rare, it appears that C. valvarum has the potential for pathogenicity in the absence of cardiac involvement.
Antimicrobial therapy is the cornerstone of management for all C. valvarum infections, and surgical consultation is warranted in cases with an obvious radiologic and/or echocardiographic nidus. The standard antimicrobial therapy for HACEK group microorganisms in existing guidelines is ceftriaxone 2 g intravenously daily for 4 weeks [23], and most reports have successfully utilized this regimen [10, 13, 15–17, 19]. The empiric choice of antimicrobial therapy has varied in published cases (Table 1), which is likely explained by local patterns of resistance, country-specific practices, and the presence or absence of embolic disease. Given the rarity of extra-cardiac manifestations, no guidelines dictate treatment of C. valvarum infection in this setting. Overall, C. valvarum appears to be susceptible to most antibiotics, with low minimum inhibitory concentrations to penicillins, cephalosporins, fluoroquinolones, and aminoglycosides [6–8, 10, 12].
Conclusions
We report a case of C. valvarum-associated aortic endograft infection, which was further complicated by vertebral discitis, epidural phlegmon, septic cerebral emboli, and the first known case of C. valvarum osteomyelitis. C. valvarum is a rare and emerging HACEK group microorganism that warrants consideration in high-risk patients with evidence of subacute infection and disseminated disease. Most cases have successfully been treated with a third-generation cephalosporin. Source control may not be feasible in cases with complex anatomy and disseminated spread.
Appendix 1
One colony of organism was suspended in 50 μl of water and boiled at 100 °C for 10 min. The cell lysate was then centrifuged at 12,000 × g for 5 min to precipitate cellular debris, and the supernatant was transferred to a new sterile tube. Polymerase chain reaction amplification and sequencing of the 860 bp fragment of 16S rRNA gene was performed with the primers 5′-GAGTTTGATYMTGGCTCAGRRYGAACGCT-3′ and 5′-GACTACCAGGGTATCTAATCC-3′, corresponding to E. coli 16S rRNA positions 9–30 and 804–783, respectively. Identification of organism was determined by matching with sequences from GenBank with the top score.
Abbreviations
CTComputed tomography
HACEKHaemophilus Spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.
MRIMagnetic resonance imaging
PCAPosterior cerebral artery
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Acknowledgements
The authors would like to thank Drs. Ramez Abdalla and Patrick Hackler for their assistance with the radiographic images.
Authors’ contributions
EGH, IN, BBY, and KMK all participated in the workup and treatment of the patient. EGH participated in the collection of data and the initial writing of the manuscript. IN and BBY performed a literature search and contributed to writing the manuscript. KMK and IN obtained pathology and radiology images. KMK reviewed the article and suggested final changes before submission. All authors read and approved the final manuscript.
Funding
This work was not supported by any external funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Declaration
Ethics approval and consent to participate
Not applicable (IRB approval is not required at Northwestern University) for case reports of a single patient. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. The patient has consented to the submission of the case report to the journal.
Consent for publication
Written and verbal consent was obtained from the patient prior to manuscript submission.
Competing interests
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. | AMLODIPINE BESYLATE, ASPIRIN, ATORVASTATIN, CARVEDILOL, EZETIMIBE, LISINOPRIL | DrugsGivenReaction | CC BY | 33639961 | 19,175,607 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhagic transformation stroke'. | An unusual case of Cardiobacterium valvarum causing aortic endograft infection and osteomyelitis.
BACKGROUND
HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.) group organisms are responsible for 0.8% to 6% of all infective endocarditis cases, with Cardiobacterium spp. being the third most commonly implicated HACEK microorganism. Within this genus is Cardiobacterium valvarum (C. valvarum), a novel organism described in 2004. To date, only 15 cases of C. valvarum infection have been reported in the English-language literature, and have primarily been cases of infective endocarditis in patients with valvular disease. C. valvarum has not been reported to cause infections spreading to the surrounding bone.
METHODS
We present a case of a 57-year-old man with a history of aortic dissection followed by aortic endograft replacement who presented with back pain. He was found to have radiographic evidence of an infected aortic endograft, along with vertebral osteomyelitis, discitis, and epidural phlegmon. Blood cultures identified C. valvarum as the causative organism. The patient was treated with ceftriaxone and surgical intervention was deferred due to the patient's complex anatomy. His course was complicated by septic cerebral emboli resulting in cerebrovascular accident.
CONCLUSIONS
This case report highlights C. valvarum, a rare and emerging HACEK group microorganism that warrants consideration in high-risk patients with evidence of subacute infection and disseminated disease. While C. valvarum classically presents as infective endocarditis, extra-cardiac manifestations have also been described. As demonstrated in this case, endograft involvement and osteomyelitis may occur in rare circumstances.
Background
Cardiobacterium spp. are fastidious, pleomorphic Gram-negative bacilli that belong to the HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.) group of microorganisms, a group of bacteria that share similar microbiological and clinical characteristics. Species within this group have been reported to be responsible for 0.8–6.0% of all infective endocarditis cases [1]. Although an uncommon cause of endocarditis overall, Cardiobacterium spp. are the third most common HACEK microorganism implicated in HACEK endocarditis [1]. Few reports of extra-cardiac Cardiobacterium spp. infection have been described [2, 3], and there are no known reports of the C. valvarum species being implicated in osteomyelitis.
Herein, we report a case of C. valvarum aortic endograft infection, which was further complicated by vertebral discitis, epidural phlegmon, septic cerebral emboli, and the first known case of C. valvarum osteomyelitis. A review of the English-language literature follows the case presentation.
Case presentation
In June 2020, a 57-year-old man was directly admitted to the hospital for radiologic evidence of vertebral osteomyelitis, discitis, and epidural phlegmon. He had a history of hypertension, hyperlipidemia, prediabetes, chronic kidney disease, and an acute Stanford Type A and Type B aortic dissection. His Type A aortic dissection (defined as involvement of the ascending aorta) had led to an emergent resection and replacement of the ascending aorta and proximal arch with a Dacron endograft nine years prior to his current presentation. Subsequent progression of an associated aortic arch aneurysm required surgical revision with a Dacron endograft exchange five years after initial surgical repair. His Type B dissection (defined as being limited to the aorta distal to the left subclavian artery without involvement of the ascending aorta) extended from the proximal aortic arch to the aortic bifurcation and remained untreated, though partially thrombosed. He had no other recent surgical instrumentation and his last dental procedure was ~ 24 months prior to his current presentation. Medications included amlodipine, aspirin, atorvastatin, carvedilol, ezetimibe, and lisinopril. He used alcohol socially and had never used tobacco or illicit drugs.
The patient had been well until ~ 6 weeks prior when isolated lower back pain developed. At that time, an outpatient non-contrast-enhanced magnetic resonance imaging (MRI) of the lumbar spine demonstrated significant edema within the vertebral bodies adjacent to the L4–L5 intervertebral disc space. Given his absence of systemic symptoms, short-term follow-up was advised. Two weeks later, a repeat contrast-enhanced MRI of the lumbar spine demonstrated progressive T2 hyperintensity at the L4–L5 intervertebral disc space and adjacent endplates with near complete involvement of the L3 and L4 vertebral bodies, highly suggestive of vertebral osteomyelitis and discitis (Fig. 1a). In addition, there was a 6 mm thick anterior epidural thickening and enhancement suggestive of epidural phlegmon that extended to L3 superiorly, S1 inferiorly, and the posterior wall of the known abdominal aortic aneurysm anteriorly (Fig. 1b). He was admitted for further workup and management.Fig. 1 Magnetic resonance imaging (MRI) of the lumbar spine demonstrating discitis and vertebral osteomyelitis. T1 post-contrast sagittal MRI demonstrating enhancement at the L3–4 intervertebral disc space with erosions in the adjacent endplates (arrow)
On admission, a temperature of 37.2 °C, heart rate of 74 beats per min, blood pressure of 129/67 mm Hg, and body-mass index of 32.7 were observed. On examination, there were multiple dental amalgam fillings and a 3/6 systolic murmur best appreciated in the aortic region, which was stable from prior. The remainder of the examination, including a focused neurologic, musculoskeletal, and dermatologic assessment, was normal. Basic laboratory tests were remarkable for anemia of inflammation, a C-reactive protein of 1.6 mg/dL (reference range, 0.0–0.5 mg/dL), an erythrocyte sedimentation rate of 53 mm/h (reference range, 3–10 mm/h), and the absence of leukocytosis. Aerobic and anaerobic peripheral blood cultures were obtained, and empiric vancomycin 1 g intravenously every 12 h and cefepime 2 g intravenously every 12 h were administered due to the proximity of the epidural phlegmon to the posterior wall of the known abdominal aortic aneurysm.
A series of diagnostic tests were subsequently performed. Computed tomography (CT) angiography of the thoracic aorta showed a soft tissue density located on the ascending aortic endograft, favored to be infectious in etiology. Transesophageal echocardiogram showed previously noted strand-like mobile echodensities on the right coronary cusp of the aortic valve, favored to represent Lambl’s excrescences (defined as thin, fibrinous structures at the lines of valve closure and postulated to be related to shear forces to the endothelium) [4]. There were no other valvular abnormalities or signs of valvular insufficiency. Contrast-enhanced CT of the face showed no evidence of dental disease. Fluoroscopy-guided bone biopsy of the L4 vertebral body obtained on day 3 of admission showed changes suggestive of resolving osteomyelitis. On day 4 of admission, 2 of 2 bottles on both sets of initial peripheral blood cultures signaled positive at 96 h of incubation. Macroscopically, colonies were described as irregular, small, round, and opaque in color. Nevertheless, due to poor growth secondary to the fastidious nature of the organism, susceptibilities were unable to be performed. Bipolar-staining pleomorphic Gram-negative rod-shaped bacilli were seen on microscopy (Fig. 2). 16S ribosomal RNA sequencing analysis subsequently identified C. valvarum (see Appendix 1 for further information regarding methods). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for further identification was not performed. Aerobic and anaerobic vertebral biopsy cultures remained negative and 16S ribosomal RNA sequencing was unfortunately not performed on these specimens. Though not definitively documented in the bone, C. valvarum identified in the blood was presumed to be the cause of the focal lesion as well.Fig. 2 Gram staining. Microscopic morphology in gram staining of blood culture after 96 h of aerobic incubation at 37 °C demonstrating bipolar-staining gram-negative bacilli. 16S ribosomal RNA (rRNA) sequencing subsequently identified the organism as Cardiobacterium valvarum
Antimicrobial therapy was changed to ceftriaxone 2 g intravenously daily and prescribed for a 6-week course. Given radiologic evidence of a possible aortic endograft nidus, a vascular surgery evaluation was obtained. Surgical intervention was ultimately deferred due to the high likelihood of extensive endograft involvement and the technical difficulty posed by the patient’s complex surgical history. The patient was discharged home on day 9 of admission with multidisciplinary follow-up and outpatient antimicrobial therapy.
Twenty days later, the patient was readmitted for acute headache and blurry vision in the left eye. MRI of the brain at that time showed a moderate-sized acute and subacute right posterior cerebral artery (PCA) territory infarct of the right occipital and posterior temporal lobes with a small focus of associated hemorrhagic transformation. Magnetic resonance angiography of the brain subsequently showed poor flow-related signal of the right PCA P3/P4 segment with a paucity of vessels in the right occipital lobe suspicious for occlusion. Monitoring of the bilateral PCAs with a 2-MHz transcranial doppler ultrasound showed nine microembolic signals within the right PCA, suspicious for septic emboli. No neurosurgical intervention was pursued, initial antithrombotic therapy was held, and repeat peripheral blood cultures were negative. Positron emission tomography–computed tomography (PET/CT) was then obtained to better characterize the aortic endograft, which showed hypermetabolic soft tissue along the right lateral and anterior aspect of the ascending aortic graft, once again suspicious for endograft infection (Fig. 3). Surgical intervention was again deferred, and the patient was discharged home on hospital day 7. He was continued on ceftriaxone 2 g intravenously daily with the addition of clopidogrel 75 mg daily and levetiracetam 1 g twice daily. He remains well in multidisciplinary outpatient follow-up with marked improvement in his back pain and no further complication. He will remain on lifelong suppressive antimicrobial therapy following his initial treatment course.Fig. 3 Positron emission tomography–computed tomography (PET/CT) of the chest. Hypermetabolic soft tissue (arrows) along the right lateral and anterior aspect of the ascending aortic endograft with a maximum standardized uptake value of 9.4, suspicious for aortic endograft infection
Discussion
The Cardiobacterium genus was first described in 1964 when its major and prior sole species, C. hominis, was recognized as a distinct microorganism by Slotnick and Dougherty [5]. C. hominis itself is a low-virulence, commensal and facultative Gram-negative bacillus that typically manifests in patients with subacute endocarditis. Historically, its microbiologic detection has been challenging due to its fastidious nature and slow-growth on traditional media.
In 2004, a novel Cardiobacterium species designated C. valvarum was isolated from the blood of a 37-year-old man with subacute endocarditis of a congenital bicuspid aortic valve and sudden rupture of a cerebral aneurysm [6]. In comparison to the major C. hominis species, C. valvarum grows more slowly, is non-hemolytic on sheep blood agar, and does not utilize sucrose, maltose, or mannitol on traditional media [6]. Since its initial recognition, there have been 15 total cases of C. valvarum infection reported in the English-language literature, all of which have utilized 16S ribosomal RNA sequencing as a means of detection [6–23]. Table 1 provides an overview of these cases. In the overwhelming majority, clinical presentations are insidious and without apparent signs of a systemic inflammatory response, such as pyrexia or chills [6, 7, 12–16]. Factors that appear to predispose patients to infection with C. valvarum include recent dental instrumentation [6, 10, 15, 16], poor dentition [9, 15, 18], and congenital cardiac disease [6, 8–10, 12, 13, 15–17, 19]. Importantly, the presence of a congenital bicuspid aortic valve appears to be strongly associated with C. valvarum pathogenicity [6, 8, 9, 13, 16, 19]. Common imaging findings in infected hosts typically include large (> 1 cm) valvular vegetations on echocardiography [6–9, 12, 16, 18, 20], and, in settings where acute neurologic dysfunction is evident, septic cerebral emboli resulting in cerebrovascular accident [6–8, 12–14, 18].Table 1 Existing case reports documenting infection by Cardiobacterium valvarum
Han et al. (2004) Hoover et al. (2005) Bothelo et al. (2006) Gonzalez et al. (2007) Geissdorfer et al. (2007) Vaněrková et al. (2010) Hoffman et al. (2010) Chen et al. (2011) Abraham et al. (2012) Choudhury et al. (2013) Pusch et al. (2015) Bonavent et al. (2016) Ni et al. (2018) Irabien et al. (2019)
Patient age 37 46 51 29 71 63 28 64 65 53 45 72 41 18
Symptoms at presentation Insidious, cardiopulmonary Insidious Insidious Insidious Insidious Insidious Insidious, cardiopulmonary Insidious Insidious, cardiopulmonary Insidious Cardiopulmonary Neurologic Cardiopulmonary Insidious
Risk factors Dental Dental, cardiac Dental, cardiac None Cardiac None Dental, cardiac Dental, cardiac None Dental, cardiac Cardiac Cardiac Dental Cardiac
Cardiac imaging findings Valvular disease, vegetations Valvular disease, reduced LVEF Vegetations,
Abscess
Valvular disease, aortic dehiscence Valvular disease, vegetations, abscess Valvular disease, vegetations Valvular disease, vegetation Valvular disease Valvular disease, vegetations Valvular disease Vegetations Valvular disease, vegetations Valvular disease, vegetations Valvular disease
Neurologic symptoms Facial Droop None None Slurred speech, numbness Weakness None None None Dysphasia, hemiplegia, facial weakness, Babinski’s sign Headache None Vision loss, confusion None None
CNS imaging findings SAH None None Acute infarcts Acute infarcts None None None vasculitis, acute infarct Acute infarcts None Acute infarct SAH, acute infarct None
Surgical intervention AVR AVR AVR AVR AVR AVR, TVA Replacement
Prosthetic
Valve-conduit
MVR None AVR None AVR MVR, TVA Repair MV, TV, ASD, RVOT Conduit
Antimicrobial
treatment
Piperacillin-tazobactam Ceftriaxone Amoxicillin,
gentamicin
Ceftriaxone,
vancomycin
Ceftriaxone,
rifampin, amikacin
Ceftriaxone,
gentamicin, cefuroxime
Ceftriaxone Cefuroxime,
gentamicin
Gentamicin, piperacillin-tazobactam Ceftriaxone, levofloxacin Ceftriaxone Penicillin, gentamicin, moxifloxacin Ceftizoxime Ceftriaxone
Clinical outcome Alive Alive Unknown Alive Deceased Alive Alive Alive Deceased Alive Alive Alive Alive Alive
CNS indicates central nervous system, LVEF left ventricular ejection fraction, SAH subarachnoid hemorrhage, AVR aortic valve replacement, MVR mitral valve replacement, TVA tricuspid valve annuloplasty, MV mitral valve, TV tricuspid valve, ASD atrial septal defect, RVOT right ventricular outflow tract
In the present case, C. valvarum bacteremia was suspected to have caused an endograft infection, later spreading to the bone. The presumed source of C. valvarum was the oral cavity given that the patient had undergone at least one dental procedure in the interim between his aortic arch surgical revision and the onset of lower back pain. While it is unclear if the patient was ever prescribed prophylactic antibiotic therapy prior to any known dental procedure, one possibility is that transient bacteremia resulting from one of these procedures seeded the aortic Dacron endograft. Transient bacteremia may also have resulted from manipulation associated with toothbrushing. The endograft may have then served as a nidus for recurrent episodes of transient bacteremia, leading to lumbar spine infection with subsequent development of osteomyelitis and contiguous spread into the epidural and intervertebral disc spaces. It should be noted that a single report of C. valvarum aortic endograft infection confirmed by 16S ribosomal RNA sequence analysis has been previously described in a 53-year-old man with total aortic arch replacement and severe aortic regurgitation in Japan [14]. Likewise, a Cardiobacterium spp (C. hominis) causing vertebral osteomyelitis, discitis, and epidural abscess has also been described [21]. To our knowledge, the present case describes the first known case of C. valvarum both affecting an aortic endograft and resulting in osteomyelitis. It should be noted that, in our case, vertebral bone biopsy cultures did not grow any organisms, although the C. valvarum identified in the blood was presumed to be the cause of the osteomyelitis as well.
In any patient with confirmed Cardiobacterium spp. infection, careful evaluation for the presence of infective endocarditis is mandatory given the high likelihood of cardiac involvement. In contrast to the majority of cases shown in Table 1 that met modified Duke criteria for “Definite” infective endocarditis, the present case was designated as “Possible” infective endocarditis by only meeting one major clinical criterion (blood cultures with a typical infective endocarditis microorganism) and two minor clinical criteria (predisposing cardiac condition and vascular phenomena) [22]. Notably, there was no echocardiographic evidence of endocardial or valvular involvement on both transthoracic and transesophageal studies. While mobile strand-like echodensities were noted on aortic valve imaging, these were favored to represent Lambl’s excrescences [4] and had been noted on previous echocardiographic examinations that predated his aortic dissection. Therefore, though rare, it appears that C. valvarum has the potential for pathogenicity in the absence of cardiac involvement.
Antimicrobial therapy is the cornerstone of management for all C. valvarum infections, and surgical consultation is warranted in cases with an obvious radiologic and/or echocardiographic nidus. The standard antimicrobial therapy for HACEK group microorganisms in existing guidelines is ceftriaxone 2 g intravenously daily for 4 weeks [23], and most reports have successfully utilized this regimen [10, 13, 15–17, 19]. The empiric choice of antimicrobial therapy has varied in published cases (Table 1), which is likely explained by local patterns of resistance, country-specific practices, and the presence or absence of embolic disease. Given the rarity of extra-cardiac manifestations, no guidelines dictate treatment of C. valvarum infection in this setting. Overall, C. valvarum appears to be susceptible to most antibiotics, with low minimum inhibitory concentrations to penicillins, cephalosporins, fluoroquinolones, and aminoglycosides [6–8, 10, 12].
Conclusions
We report a case of C. valvarum-associated aortic endograft infection, which was further complicated by vertebral discitis, epidural phlegmon, septic cerebral emboli, and the first known case of C. valvarum osteomyelitis. C. valvarum is a rare and emerging HACEK group microorganism that warrants consideration in high-risk patients with evidence of subacute infection and disseminated disease. Most cases have successfully been treated with a third-generation cephalosporin. Source control may not be feasible in cases with complex anatomy and disseminated spread.
Appendix 1
One colony of organism was suspended in 50 μl of water and boiled at 100 °C for 10 min. The cell lysate was then centrifuged at 12,000 × g for 5 min to precipitate cellular debris, and the supernatant was transferred to a new sterile tube. Polymerase chain reaction amplification and sequencing of the 860 bp fragment of 16S rRNA gene was performed with the primers 5′-GAGTTTGATYMTGGCTCAGRRYGAACGCT-3′ and 5′-GACTACCAGGGTATCTAATCC-3′, corresponding to E. coli 16S rRNA positions 9–30 and 804–783, respectively. Identification of organism was determined by matching with sequences from GenBank with the top score.
Abbreviations
CTComputed tomography
HACEKHaemophilus Spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.
MRIMagnetic resonance imaging
PCAPosterior cerebral artery
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank Drs. Ramez Abdalla and Patrick Hackler for their assistance with the radiographic images.
Authors’ contributions
EGH, IN, BBY, and KMK all participated in the workup and treatment of the patient. EGH participated in the collection of data and the initial writing of the manuscript. IN and BBY performed a literature search and contributed to writing the manuscript. KMK and IN obtained pathology and radiology images. KMK reviewed the article and suggested final changes before submission. All authors read and approved the final manuscript.
Funding
This work was not supported by any external funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Declaration
Ethics approval and consent to participate
Not applicable (IRB approval is not required at Northwestern University) for case reports of a single patient. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. The patient has consented to the submission of the case report to the journal.
Consent for publication
Written and verbal consent was obtained from the patient prior to manuscript submission.
Competing interests
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. | AMLODIPINE BESYLATE, ASPIRIN, ATORVASTATIN, CARVEDILOL, EZETIMIBE, LISINOPRIL | DrugsGivenReaction | CC BY | 33639961 | 19,175,607 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vascular graft infection'. | An unusual case of Cardiobacterium valvarum causing aortic endograft infection and osteomyelitis.
BACKGROUND
HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.) group organisms are responsible for 0.8% to 6% of all infective endocarditis cases, with Cardiobacterium spp. being the third most commonly implicated HACEK microorganism. Within this genus is Cardiobacterium valvarum (C. valvarum), a novel organism described in 2004. To date, only 15 cases of C. valvarum infection have been reported in the English-language literature, and have primarily been cases of infective endocarditis in patients with valvular disease. C. valvarum has not been reported to cause infections spreading to the surrounding bone.
METHODS
We present a case of a 57-year-old man with a history of aortic dissection followed by aortic endograft replacement who presented with back pain. He was found to have radiographic evidence of an infected aortic endograft, along with vertebral osteomyelitis, discitis, and epidural phlegmon. Blood cultures identified C. valvarum as the causative organism. The patient was treated with ceftriaxone and surgical intervention was deferred due to the patient's complex anatomy. His course was complicated by septic cerebral emboli resulting in cerebrovascular accident.
CONCLUSIONS
This case report highlights C. valvarum, a rare and emerging HACEK group microorganism that warrants consideration in high-risk patients with evidence of subacute infection and disseminated disease. While C. valvarum classically presents as infective endocarditis, extra-cardiac manifestations have also been described. As demonstrated in this case, endograft involvement and osteomyelitis may occur in rare circumstances.
Background
Cardiobacterium spp. are fastidious, pleomorphic Gram-negative bacilli that belong to the HACEK (Haemophilus spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.) group of microorganisms, a group of bacteria that share similar microbiological and clinical characteristics. Species within this group have been reported to be responsible for 0.8–6.0% of all infective endocarditis cases [1]. Although an uncommon cause of endocarditis overall, Cardiobacterium spp. are the third most common HACEK microorganism implicated in HACEK endocarditis [1]. Few reports of extra-cardiac Cardiobacterium spp. infection have been described [2, 3], and there are no known reports of the C. valvarum species being implicated in osteomyelitis.
Herein, we report a case of C. valvarum aortic endograft infection, which was further complicated by vertebral discitis, epidural phlegmon, septic cerebral emboli, and the first known case of C. valvarum osteomyelitis. A review of the English-language literature follows the case presentation.
Case presentation
In June 2020, a 57-year-old man was directly admitted to the hospital for radiologic evidence of vertebral osteomyelitis, discitis, and epidural phlegmon. He had a history of hypertension, hyperlipidemia, prediabetes, chronic kidney disease, and an acute Stanford Type A and Type B aortic dissection. His Type A aortic dissection (defined as involvement of the ascending aorta) had led to an emergent resection and replacement of the ascending aorta and proximal arch with a Dacron endograft nine years prior to his current presentation. Subsequent progression of an associated aortic arch aneurysm required surgical revision with a Dacron endograft exchange five years after initial surgical repair. His Type B dissection (defined as being limited to the aorta distal to the left subclavian artery without involvement of the ascending aorta) extended from the proximal aortic arch to the aortic bifurcation and remained untreated, though partially thrombosed. He had no other recent surgical instrumentation and his last dental procedure was ~ 24 months prior to his current presentation. Medications included amlodipine, aspirin, atorvastatin, carvedilol, ezetimibe, and lisinopril. He used alcohol socially and had never used tobacco or illicit drugs.
The patient had been well until ~ 6 weeks prior when isolated lower back pain developed. At that time, an outpatient non-contrast-enhanced magnetic resonance imaging (MRI) of the lumbar spine demonstrated significant edema within the vertebral bodies adjacent to the L4–L5 intervertebral disc space. Given his absence of systemic symptoms, short-term follow-up was advised. Two weeks later, a repeat contrast-enhanced MRI of the lumbar spine demonstrated progressive T2 hyperintensity at the L4–L5 intervertebral disc space and adjacent endplates with near complete involvement of the L3 and L4 vertebral bodies, highly suggestive of vertebral osteomyelitis and discitis (Fig. 1a). In addition, there was a 6 mm thick anterior epidural thickening and enhancement suggestive of epidural phlegmon that extended to L3 superiorly, S1 inferiorly, and the posterior wall of the known abdominal aortic aneurysm anteriorly (Fig. 1b). He was admitted for further workup and management.Fig. 1 Magnetic resonance imaging (MRI) of the lumbar spine demonstrating discitis and vertebral osteomyelitis. T1 post-contrast sagittal MRI demonstrating enhancement at the L3–4 intervertebral disc space with erosions in the adjacent endplates (arrow)
On admission, a temperature of 37.2 °C, heart rate of 74 beats per min, blood pressure of 129/67 mm Hg, and body-mass index of 32.7 were observed. On examination, there were multiple dental amalgam fillings and a 3/6 systolic murmur best appreciated in the aortic region, which was stable from prior. The remainder of the examination, including a focused neurologic, musculoskeletal, and dermatologic assessment, was normal. Basic laboratory tests were remarkable for anemia of inflammation, a C-reactive protein of 1.6 mg/dL (reference range, 0.0–0.5 mg/dL), an erythrocyte sedimentation rate of 53 mm/h (reference range, 3–10 mm/h), and the absence of leukocytosis. Aerobic and anaerobic peripheral blood cultures were obtained, and empiric vancomycin 1 g intravenously every 12 h and cefepime 2 g intravenously every 12 h were administered due to the proximity of the epidural phlegmon to the posterior wall of the known abdominal aortic aneurysm.
A series of diagnostic tests were subsequently performed. Computed tomography (CT) angiography of the thoracic aorta showed a soft tissue density located on the ascending aortic endograft, favored to be infectious in etiology. Transesophageal echocardiogram showed previously noted strand-like mobile echodensities on the right coronary cusp of the aortic valve, favored to represent Lambl’s excrescences (defined as thin, fibrinous structures at the lines of valve closure and postulated to be related to shear forces to the endothelium) [4]. There were no other valvular abnormalities or signs of valvular insufficiency. Contrast-enhanced CT of the face showed no evidence of dental disease. Fluoroscopy-guided bone biopsy of the L4 vertebral body obtained on day 3 of admission showed changes suggestive of resolving osteomyelitis. On day 4 of admission, 2 of 2 bottles on both sets of initial peripheral blood cultures signaled positive at 96 h of incubation. Macroscopically, colonies were described as irregular, small, round, and opaque in color. Nevertheless, due to poor growth secondary to the fastidious nature of the organism, susceptibilities were unable to be performed. Bipolar-staining pleomorphic Gram-negative rod-shaped bacilli were seen on microscopy (Fig. 2). 16S ribosomal RNA sequencing analysis subsequently identified C. valvarum (see Appendix 1 for further information regarding methods). Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for further identification was not performed. Aerobic and anaerobic vertebral biopsy cultures remained negative and 16S ribosomal RNA sequencing was unfortunately not performed on these specimens. Though not definitively documented in the bone, C. valvarum identified in the blood was presumed to be the cause of the focal lesion as well.Fig. 2 Gram staining. Microscopic morphology in gram staining of blood culture after 96 h of aerobic incubation at 37 °C demonstrating bipolar-staining gram-negative bacilli. 16S ribosomal RNA (rRNA) sequencing subsequently identified the organism as Cardiobacterium valvarum
Antimicrobial therapy was changed to ceftriaxone 2 g intravenously daily and prescribed for a 6-week course. Given radiologic evidence of a possible aortic endograft nidus, a vascular surgery evaluation was obtained. Surgical intervention was ultimately deferred due to the high likelihood of extensive endograft involvement and the technical difficulty posed by the patient’s complex surgical history. The patient was discharged home on day 9 of admission with multidisciplinary follow-up and outpatient antimicrobial therapy.
Twenty days later, the patient was readmitted for acute headache and blurry vision in the left eye. MRI of the brain at that time showed a moderate-sized acute and subacute right posterior cerebral artery (PCA) territory infarct of the right occipital and posterior temporal lobes with a small focus of associated hemorrhagic transformation. Magnetic resonance angiography of the brain subsequently showed poor flow-related signal of the right PCA P3/P4 segment with a paucity of vessels in the right occipital lobe suspicious for occlusion. Monitoring of the bilateral PCAs with a 2-MHz transcranial doppler ultrasound showed nine microembolic signals within the right PCA, suspicious for septic emboli. No neurosurgical intervention was pursued, initial antithrombotic therapy was held, and repeat peripheral blood cultures were negative. Positron emission tomography–computed tomography (PET/CT) was then obtained to better characterize the aortic endograft, which showed hypermetabolic soft tissue along the right lateral and anterior aspect of the ascending aortic graft, once again suspicious for endograft infection (Fig. 3). Surgical intervention was again deferred, and the patient was discharged home on hospital day 7. He was continued on ceftriaxone 2 g intravenously daily with the addition of clopidogrel 75 mg daily and levetiracetam 1 g twice daily. He remains well in multidisciplinary outpatient follow-up with marked improvement in his back pain and no further complication. He will remain on lifelong suppressive antimicrobial therapy following his initial treatment course.Fig. 3 Positron emission tomography–computed tomography (PET/CT) of the chest. Hypermetabolic soft tissue (arrows) along the right lateral and anterior aspect of the ascending aortic endograft with a maximum standardized uptake value of 9.4, suspicious for aortic endograft infection
Discussion
The Cardiobacterium genus was first described in 1964 when its major and prior sole species, C. hominis, was recognized as a distinct microorganism by Slotnick and Dougherty [5]. C. hominis itself is a low-virulence, commensal and facultative Gram-negative bacillus that typically manifests in patients with subacute endocarditis. Historically, its microbiologic detection has been challenging due to its fastidious nature and slow-growth on traditional media.
In 2004, a novel Cardiobacterium species designated C. valvarum was isolated from the blood of a 37-year-old man with subacute endocarditis of a congenital bicuspid aortic valve and sudden rupture of a cerebral aneurysm [6]. In comparison to the major C. hominis species, C. valvarum grows more slowly, is non-hemolytic on sheep blood agar, and does not utilize sucrose, maltose, or mannitol on traditional media [6]. Since its initial recognition, there have been 15 total cases of C. valvarum infection reported in the English-language literature, all of which have utilized 16S ribosomal RNA sequencing as a means of detection [6–23]. Table 1 provides an overview of these cases. In the overwhelming majority, clinical presentations are insidious and without apparent signs of a systemic inflammatory response, such as pyrexia or chills [6, 7, 12–16]. Factors that appear to predispose patients to infection with C. valvarum include recent dental instrumentation [6, 10, 15, 16], poor dentition [9, 15, 18], and congenital cardiac disease [6, 8–10, 12, 13, 15–17, 19]. Importantly, the presence of a congenital bicuspid aortic valve appears to be strongly associated with C. valvarum pathogenicity [6, 8, 9, 13, 16, 19]. Common imaging findings in infected hosts typically include large (> 1 cm) valvular vegetations on echocardiography [6–9, 12, 16, 18, 20], and, in settings where acute neurologic dysfunction is evident, septic cerebral emboli resulting in cerebrovascular accident [6–8, 12–14, 18].Table 1 Existing case reports documenting infection by Cardiobacterium valvarum
Han et al. (2004) Hoover et al. (2005) Bothelo et al. (2006) Gonzalez et al. (2007) Geissdorfer et al. (2007) Vaněrková et al. (2010) Hoffman et al. (2010) Chen et al. (2011) Abraham et al. (2012) Choudhury et al. (2013) Pusch et al. (2015) Bonavent et al. (2016) Ni et al. (2018) Irabien et al. (2019)
Patient age 37 46 51 29 71 63 28 64 65 53 45 72 41 18
Symptoms at presentation Insidious, cardiopulmonary Insidious Insidious Insidious Insidious Insidious Insidious, cardiopulmonary Insidious Insidious, cardiopulmonary Insidious Cardiopulmonary Neurologic Cardiopulmonary Insidious
Risk factors Dental Dental, cardiac Dental, cardiac None Cardiac None Dental, cardiac Dental, cardiac None Dental, cardiac Cardiac Cardiac Dental Cardiac
Cardiac imaging findings Valvular disease, vegetations Valvular disease, reduced LVEF Vegetations,
Abscess
Valvular disease, aortic dehiscence Valvular disease, vegetations, abscess Valvular disease, vegetations Valvular disease, vegetation Valvular disease Valvular disease, vegetations Valvular disease Vegetations Valvular disease, vegetations Valvular disease, vegetations Valvular disease
Neurologic symptoms Facial Droop None None Slurred speech, numbness Weakness None None None Dysphasia, hemiplegia, facial weakness, Babinski’s sign Headache None Vision loss, confusion None None
CNS imaging findings SAH None None Acute infarcts Acute infarcts None None None vasculitis, acute infarct Acute infarcts None Acute infarct SAH, acute infarct None
Surgical intervention AVR AVR AVR AVR AVR AVR, TVA Replacement
Prosthetic
Valve-conduit
MVR None AVR None AVR MVR, TVA Repair MV, TV, ASD, RVOT Conduit
Antimicrobial
treatment
Piperacillin-tazobactam Ceftriaxone Amoxicillin,
gentamicin
Ceftriaxone,
vancomycin
Ceftriaxone,
rifampin, amikacin
Ceftriaxone,
gentamicin, cefuroxime
Ceftriaxone Cefuroxime,
gentamicin
Gentamicin, piperacillin-tazobactam Ceftriaxone, levofloxacin Ceftriaxone Penicillin, gentamicin, moxifloxacin Ceftizoxime Ceftriaxone
Clinical outcome Alive Alive Unknown Alive Deceased Alive Alive Alive Deceased Alive Alive Alive Alive Alive
CNS indicates central nervous system, LVEF left ventricular ejection fraction, SAH subarachnoid hemorrhage, AVR aortic valve replacement, MVR mitral valve replacement, TVA tricuspid valve annuloplasty, MV mitral valve, TV tricuspid valve, ASD atrial septal defect, RVOT right ventricular outflow tract
In the present case, C. valvarum bacteremia was suspected to have caused an endograft infection, later spreading to the bone. The presumed source of C. valvarum was the oral cavity given that the patient had undergone at least one dental procedure in the interim between his aortic arch surgical revision and the onset of lower back pain. While it is unclear if the patient was ever prescribed prophylactic antibiotic therapy prior to any known dental procedure, one possibility is that transient bacteremia resulting from one of these procedures seeded the aortic Dacron endograft. Transient bacteremia may also have resulted from manipulation associated with toothbrushing. The endograft may have then served as a nidus for recurrent episodes of transient bacteremia, leading to lumbar spine infection with subsequent development of osteomyelitis and contiguous spread into the epidural and intervertebral disc spaces. It should be noted that a single report of C. valvarum aortic endograft infection confirmed by 16S ribosomal RNA sequence analysis has been previously described in a 53-year-old man with total aortic arch replacement and severe aortic regurgitation in Japan [14]. Likewise, a Cardiobacterium spp (C. hominis) causing vertebral osteomyelitis, discitis, and epidural abscess has also been described [21]. To our knowledge, the present case describes the first known case of C. valvarum both affecting an aortic endograft and resulting in osteomyelitis. It should be noted that, in our case, vertebral bone biopsy cultures did not grow any organisms, although the C. valvarum identified in the blood was presumed to be the cause of the osteomyelitis as well.
In any patient with confirmed Cardiobacterium spp. infection, careful evaluation for the presence of infective endocarditis is mandatory given the high likelihood of cardiac involvement. In contrast to the majority of cases shown in Table 1 that met modified Duke criteria for “Definite” infective endocarditis, the present case was designated as “Possible” infective endocarditis by only meeting one major clinical criterion (blood cultures with a typical infective endocarditis microorganism) and two minor clinical criteria (predisposing cardiac condition and vascular phenomena) [22]. Notably, there was no echocardiographic evidence of endocardial or valvular involvement on both transthoracic and transesophageal studies. While mobile strand-like echodensities were noted on aortic valve imaging, these were favored to represent Lambl’s excrescences [4] and had been noted on previous echocardiographic examinations that predated his aortic dissection. Therefore, though rare, it appears that C. valvarum has the potential for pathogenicity in the absence of cardiac involvement.
Antimicrobial therapy is the cornerstone of management for all C. valvarum infections, and surgical consultation is warranted in cases with an obvious radiologic and/or echocardiographic nidus. The standard antimicrobial therapy for HACEK group microorganisms in existing guidelines is ceftriaxone 2 g intravenously daily for 4 weeks [23], and most reports have successfully utilized this regimen [10, 13, 15–17, 19]. The empiric choice of antimicrobial therapy has varied in published cases (Table 1), which is likely explained by local patterns of resistance, country-specific practices, and the presence or absence of embolic disease. Given the rarity of extra-cardiac manifestations, no guidelines dictate treatment of C. valvarum infection in this setting. Overall, C. valvarum appears to be susceptible to most antibiotics, with low minimum inhibitory concentrations to penicillins, cephalosporins, fluoroquinolones, and aminoglycosides [6–8, 10, 12].
Conclusions
We report a case of C. valvarum-associated aortic endograft infection, which was further complicated by vertebral discitis, epidural phlegmon, septic cerebral emboli, and the first known case of C. valvarum osteomyelitis. C. valvarum is a rare and emerging HACEK group microorganism that warrants consideration in high-risk patients with evidence of subacute infection and disseminated disease. Most cases have successfully been treated with a third-generation cephalosporin. Source control may not be feasible in cases with complex anatomy and disseminated spread.
Appendix 1
One colony of organism was suspended in 50 μl of water and boiled at 100 °C for 10 min. The cell lysate was then centrifuged at 12,000 × g for 5 min to precipitate cellular debris, and the supernatant was transferred to a new sterile tube. Polymerase chain reaction amplification and sequencing of the 860 bp fragment of 16S rRNA gene was performed with the primers 5′-GAGTTTGATYMTGGCTCAGRRYGAACGCT-3′ and 5′-GACTACCAGGGTATCTAATCC-3′, corresponding to E. coli 16S rRNA positions 9–30 and 804–783, respectively. Identification of organism was determined by matching with sequences from GenBank with the top score.
Abbreviations
CTComputed tomography
HACEKHaemophilus Spp., Aggregatibacter spp., Cardiobacterium spp., Eikenella corrodens, and Kingella spp.
MRIMagnetic resonance imaging
PCAPosterior cerebral artery
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank Drs. Ramez Abdalla and Patrick Hackler for their assistance with the radiographic images.
Authors’ contributions
EGH, IN, BBY, and KMK all participated in the workup and treatment of the patient. EGH participated in the collection of data and the initial writing of the manuscript. IN and BBY performed a literature search and contributed to writing the manuscript. KMK and IN obtained pathology and radiology images. KMK reviewed the article and suggested final changes before submission. All authors read and approved the final manuscript.
Funding
This work was not supported by any external funding.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Declaration
Ethics approval and consent to participate
Not applicable (IRB approval is not required at Northwestern University) for case reports of a single patient. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. The patient has consented to the submission of the case report to the journal.
Consent for publication
Written and verbal consent was obtained from the patient prior to manuscript submission.
Competing interests
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper. | AMLODIPINE BESYLATE, ASPIRIN, ATORVASTATIN, CARVEDILOL, EZETIMIBE, LISINOPRIL | DrugsGivenReaction | CC BY | 33639961 | 19,175,607 | 2021-02-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory failure'. | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | CYCLOSPORINE, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33641488 | 19,179,180 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Eosinophilic pneumonia'. | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | CYCLOSPORINE, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33641488 | 19,179,180 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Live birth'. | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | CYCLOSPORINE, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33641488 | 19,179,180 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | CYCLOSPORINE, PREDNISOLONE | DrugsGivenReaction | CC BY-NC | 33641488 | 19,179,180 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Meningitis viral'. | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | CYCLOSPORINE, METHOTREXATE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33641488 | 19,169,598 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | CYCLOSPORINE, METHOTREXATE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33641488 | 19,169,598 | 2021-02 |
What was the administration route of drug 'PREDNISOLONE'? | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | Oral | DrugAdministrationRoute | CC BY-NC | 33641488 | 19,169,598 | 2021-02 |
What was the outcome of reaction 'Acute respiratory failure'? | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | Recovered | ReactionOutcome | CC BY-NC | 33641488 | 19,179,180 | 2021-02 |
What was the outcome of reaction 'Eosinophilic pneumonia'? | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | Recovered | ReactionOutcome | CC BY-NC | 33641488 | 19,179,180 | 2021-02 |
What was the outcome of reaction 'Meningitis viral'? | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | Recovered | ReactionOutcome | CC BY-NC | 33641488 | 19,169,598 | 2021-02 |
What was the outcome of reaction 'Peripheral T-cell lymphoma unspecified'? | CCR4-positive peripheral T-cell lymphoma presenting as eosinophilic pneumonia and developing from prolonged pustular psoriasis.
A 29-year-old woman with chronic, prolonged pustular psoriasis was admitted to our hospital because of high-grade fever and a systemic skin rash. General examination revealed a whole-body skin rash and superficial lymphadenopathy. Peripheral blood examination showed unclassified cells positive for CD3, CD4, and T-cell receptor αβ, and negative for CD20 and CD56. Soon after administration, she developed acute respiratory failure and required artificial ventilation. Bronchoalveolar lavage fluid showed increased numbers of eosinophils and abnormal lymphocytes of the same phenotype in peripheral blood and skin. She was diagnosed with eosinophilic pneumonia, and her respiratory failure was improved by corticosteroid therapy. Based on the histological findings of skin, lymph node, and bone marrow biopsies, a diagnosis of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), with positivity for CC chemokine receptor 4 was made. She received chemotherapy followed by allogeneic stem cell transplantation, which resulted in complete remission of her PTCL-NOS. She remained alive and disease-free 6 years later. This is the first reported case of PTCL-NOS developing during the clinical course of pustular psoriasis. The clinical manifestations of PTCL-NOS are complex, but an accurate diagnosis and appropriate therapy may produce a good clinical outcome in patients with PTCL-NOS.
Introduction
Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a heterogeneous category of nodal and mature T-cell lymphomas that do not correspond to any of the specifically defined entities of mature T-cell lymphoma in the current classification.1,2 PTCL-NOS is the most common PTCL subtype, accounting for at least 25% of all cases of PTCL.3Although PTCL-NOS is a clinically rare disease, it has various clinical manifestations, including impaired immune surveillance,1–3 secondary malignancies,4 Epstein–Barr virus (EBV) infection,1–4 and/or peripheral eosinophilia.1–3,5 In addition, the prognosis of PTCL-NOS is generally poor, with a 5-year overall survival of only 20%–30%.1–3 Furthermore, expression of CC chemokine receptor 4 (CCR4) was shown to be associated with a shorter survival time, compared with patients with CCR4-negative PTCL-NOS.6,7 The diagnosis and optimal treatment of PTCL-NOS are thus challenging because of the complexity of the clinical manifestations and the potentially poor prognosis.
We report a case of CCR4-positive PTCL-NOS that developed from chronic and prolonged pustular psoriasis, which had been treated with prednisolone and cyclosporine A. The patient presented with acute eosinophilic pneumonia at the initial diagnosis. Respiratory failure was improved by corticosteroid therapy, and subsequent chemotherapy followed by allogeneic stem cell transplantation resulted in complete remission of her PTCL-NOS for over 5 years. We here describe the clinical course and review the relevant literature.
Case report
A 29-year-old woman was admitted to our hospital with general fatigue, high fever, and a skin rash. She had suffered from pustular psoriasis since she was less than 1 year old, based on typical dermatological and histopathological findings. She had been treated with prednisolone and cyclosporine A to control the disease for over 25 years. She gave birth when she was 27, and oral prednisolone was gradually reduced and stopped 6 months after the birth. However, she developed low-grade fever and skin rash on her face 15 months after the delivery. She received oral antibiotics, but her fever did not improve and her skin rash worsened. She was admitted to our hospital for further examination. Physical examination revealed remittent fever (38.0°C), red papules and nodules on her skin (Figure 1), hepatomegaly, and superficial lymphadenopathies. Laboratory findings revealed leukocytosis (17,460/µL) and 30% abnormal and unclassified cells in her peripheral blood. Other findings included lactate dehydrogenase 945 IU/L, and soluble interleukin (IL)-2 receptor 2,079 U/mL (normal range, 135–421 U/mL). Human immunodeficiency virus and human T-cell lymphotropic virus antibodies were negative, and EBV DNA was undetectable by real-time polymerase chain reaction. Contrast-enhanced computed tomography (CT) scan revealed hepatosplenomegaly and superficial lymphadenopathy (Figure 2). (18F)-Fluorodeoxyglucose (FDG) positron emission tomography/CT scan showed increased FDG uptake in whole-body lymph nodes, spleen, liver, and bone marrow (Figure 3). Flow cytometric analysis revealed that the peripheral unclassified cells were positive for CD3, CD4, CD5, CD8, and T-cell receptor (TCR) αβ, and negative for CD20 and CD56. We performed skin, lymph node, and bone marrow biopsies. Flow cytometry analysis of each specimen showed CD3-, CD4-, CD5-, and TCRαβ-positive abnormal cells. Soon after these examinations, her peripheral eosinophils increased from 644/µL to 2949/µL after hospitalization, and her respiratory condition deteriorated rapidly. Chest radiography and CT scan (Figure 4a and 4b) revealed diffuse infiltrative shadows in the bilateral lungs. She developed acute respiratory failure and needed ventilator management in the intensive care unit. Bronchoscopy was performed and bronchoalveolar lavage fluid (BALF) revealed total cells of 16.9 × 105/mL, with differential counts of alveolar macrophages (27.2%), abnormal lymphocytes (28.6%), neutrophils (1.1%), and eosinophils (43.1%). The infiltrated lymphocytes in the lung were positive for CD3, CD4, CD5, and TCRαβ, similar to the abnormal peripheral blood cells. Based on the radiological findings and the increased eosinophils in the plasma and BALF, we speculated that the respiratory involvement might indicate eosinophilic pneumonia and infiltration of unclassified malignant lymphocytes. Corticosteroid pulse therapy was initiated under respirator management. Her respiration improved and she no longer required respirator assistance after 9 days of corticosteroid therapy (Figure 4c). While managing her respiratory impairment, the biopsy specimens (skin, lymph node, bone marrow) demonstrated CCR4-positive PTCL-NOS (Figure 5).
Figure 1. Reddish papules and nodules were observed on the whole skin in the present case.
Figure 2. Computed tomography identified hepatosplenomegaly and superficial lymphadenopathy (yellow arrows).
Figure 3. Positron emission tomography with fluorodeoxyglucose (FDG)-computed tomography revealed increased FDG uptake in the lymph nodes, spleen, liver, and bone marrow.
Figure 4. Imaging before and after steroid therapy. Chest radiograph (a) and computed tomography scan (b) revealed diffuse infiltrative shadows in bilateral lungs. The infiltrative shadows disappeared after steroid therapy (c).
Figure 5. Histopathological findings in resected inguinal lymph nodes upon diagnosis of peripheral T-cell lymphoma not otherwise specified, showing diffuse proliferations of lymphoid cells positive for CD4 and CC chemokine 4 (CCR4), and negative for CD20.
H.E, hematoxylin and eosin; TIA1, T-cell intracellular antigen 1; CXCL14, C-X-C motif chemokine ligand 14; PD1, programmed cell death protein 1; EBER, Epstein–Barr virus-encoded small RNAs.
After the diagnosis, the patient received six cycles of CHOEP-14 chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, etoposide), with no specific toxicities, resulting in no abnormal cells in the peripheral blood and bone marrow. She then underwent myeloablative conditioning and allogeneic stem cell transplantation, with peripheral blood stem cells from an HLA fully matched donor. Tacrolimus and methotrexate were used as immunosuppressants to prevent graft-versus-host disease, followed by prednisolone. Bone marrow examination after stem cell transplantation confirmed complete remission. She was discharged from hospital 54 days after her stem cell transplant. She developed acute pancreatitis during hospitalization and viral meningitis after hospitalization, but these complications improved following appropriate treatments. Her skin involvement due to pustular psoriasis was mild during prednisolone therapy (5–10 mg/day), and she remained alive 6 years after her stem cell transplant.
We retrospectively measured IL-5 levels in the plasma and BALF at the onset of acute respiratory failure. Her BALF and plasma IL-5 levels were 469 pg/mL and 164 pg/mL, respectively, just before steroid treatment. The plasma IL-5 was higher than 2 weeks before (<3.9 pg/mL) and 3 weeks after (<3.9 pg/mL) the onset of acute eosinophilic pneumonia.
Discussion
We report on a young woman who developed PTCL-NOS during prolonged treatment with prednisolone and cyclosporine A for pustular psoriasis. There is a relationship between the use of immunosuppressive therapies and the development of lymphoproliferative malignancies, including PTCL.1–3,8,9 However, most cases involve classical immunosuppressive treatments including cyclosporine A and methotrexate,8 and the resulting lymphomas are mainly B-cell non-Hodgkin's lymphomas associated with EBV infection.9
The median age at presentation of PTCL-NOS is approximately 60 years, with a male predominance.1 Unusually therefore, the current case was a young female with undetectable EBV. We speculated that the development of PTCL-NOS in this case was associated with prolonged cyclosporine A therapy for pustular psoriasis. We searched the PubMed database using the keywords “pustular psoriasis” and “PTCL”, but found no similar reports. To the best of our knowledge therefore, this case provides the first report of PTCL-NOS in a patient with a history of pustular psoriasis. Notably, the current patient also showed expression of CCR4. CCR4 is generally highly expressed in mature T-cell lymphomas, such as adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.10 Although the mechanism or interaction was unknown, the expression of CCR4 in the present case of PTLC-NOS might also have been related to the prolonged therapy with immunosuppressants and/or clinical inflammation associated with pustular psoriasis.
Most patients with PTCL-NOS present with advanced disease and have a poor prognosis, with a 5-year overall survival of only 20% to 30%.1–3,11 In addition, patients with CCR4-positive lymphomas have a significantly shorter survival time compared with CCR4-negative patients6,7 The present patient had a good clinical outcome after CHOEP chemotherapy and allogeneic stem cell transplantation. The addition of etoposide to CHOP previously improved the treatment-free interval compared with CHOP therapy in a subset of young patients with PTCL-NOS.3 Although the heterogeneity and rarity of PTCL-NOS mean there is currently no standard treatment, allogeneic stem cell transplant therapy is considered to be a novel therapeutic option for PTCL-NOS.12,13 The current case provides important additional information, but further case series are needed.
Eosinophilic pneumonia involves pulmonary infiltration of the lung by eosinophils. The etiology of this disease has been related to helminth infections, drugs, environmental exposure, and collagen disease.14 Although eosinophilic pulmonary infiltration in patients with malignant lymphoma is extremely rare, several cases of eosinophilic pneumonia have been reported in patients with T-cell lymphoma.5,15,16 Eosinophilia is probably secondary to the production of cytokines including IL 4–6 and 10 by YH2 cells.14 IL-5 levels in the BALF were found to be increased in several patients with eosinophilic pneumonia15–17; however, the level in the current case was higher than in other reports.15–17 The proportion of CCR4-expressing T cells among CD4+ T cells was higher in BALF than in the peripheral blood in patients with eosinophilic pneumonia,15 and there was a significant correlation between the number of CCR4+ CD4+ T cells and IL-5 levels in the BALF in patients with eosinophilic pneumonia.15 Tumor-cell derived IL-5 in the present case might thus be related to the development of eosinophilic pneumonia, while CCR4 might play an important role in the onset of eosinophilic pneumonia in patients with T cell lymphoma. Further studies are needed to determine the role of CCR4 in eosinophilic pneumonia.
Conclusion
We report a case of CCR4-positive PTCL-NOS that developed during the clinical course of pustular psoriasis. Although the diagnosis and management of PTCL-NOS are difficult owing to the complexity of the disease, this case highlights eosinophilic pneumonia as a possible complication, and pustular psoriasis as an underlying disease of PTCL-NOS. In addition, appropriate treatment, including bone marrow transplantation, could improve the clinical outcome. It is therefore necessary to be aware of the presence and clinical features of PTCL-NOS.
Ethics statement: The patient provided written informed consent for all the treatment procedures and for publication of this case report and any accompanying images. Ethical approval by the institutional research committee was not relevant or applicable for this case report.
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
ORCID iD: Tomonobu Koizumi https://orcid.org/0000-0002-5182-0960 | Recovered | ReactionOutcome | CC BY-NC | 33641488 | 19,169,598 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Loss of consciousness'. | Polymorphic Ventricular Tachycardia with QT Interval Prolongation Due to a Brain Tumor.
We herein report the case of a 20-year-old man with a history of epilepsy who presented with frequent transient loss of consciousness (T-LOC) and polymorphic ventricular tachycardia (VT) with QT interval prolongation. Blood investigations revealed panhypopituitarism. Following a biopsy, he was diagnosed with brain germinoma. During the biopsy, he had an episode of polymorphous VT with QT prolongation. There was no recurrence of T-LOC following chemotherapy and hormone replacement therapy. This case indicates the importance of checking the QT interval in patients with T-LOC, including those with seizures and brain tumors, to ensure appropriate treatment.
pmcIntroduction
Long QT syndrome (LQTS) can be congenital or acquired. The causes of acquired LQTS are diverse, including drugs, metabolic and electrolyte abnormalities, heart disease, and central nervous system disorders. Electrolyte abnormalities include hypokalemia, hypomagnesemia, and hypocalcemia. Hypopituitarism might lead to electrolyte abnormalities, and there are several reports of loss of consciousness due to hypopituitarism (1-3).
We herein report a case of QT prolongation caused by electrolyte abnormalities associated with hypopituitarism due to a pituitary tumor.
Case Report
A 20-year-old man with a history of epilepsy was diagnosed with a brain tumor and referred to our neurosurgical department for treatment. He began to experience episodes of transient loss of consciousness (T-LOC) for 1 year and 3 months almost twice a week despite taking antiepileptic drugs (Sodium valproate 800 mg, and Levetiracetam 1,000 mg). These episodes occurred both at rest and during exercise. An electrocardiogram (ECG) abnormality had been noted in his records two years before the onset of T-LOC. A pituitary tumor was identified on magnetic resonance imaging (MRI), and he was subsequently referred to the neurosurgery department for a biopsy. He had no family history of sudden death or structural heart disease.
On admission, his ECG (Fig. 1) showed sinus rhythm with a heart rate of 60 beats per minute, and the corrected QT (QTc) interval was prolonged to 519 ms. An echocardiogram showed a normal ventricular function with no structural heart disease. Blood investigations (Table) revealed panhypopituitarism, including hypopituitarism, hypoadrenalism, and hypothyroidism. He had hypokalemia at the time of admission but recovered spontaneously without treatment (Fig. 2).
Figure 1. His electrocardiogram on admission showed sinus rhythm with a heart rate of 60 times, and the corrected QT interval prolonged to 519 ms. QRS complexes were without any abnormality.
Table. Patient's Laboratory Data.
Laboratory data on admission
Complete blood count
White blood cells 6,800 /μL
Red blood cells 380×10^4 /μL
Hemoglobin 11.8 g/dL
Platelets 109×10^3 /μL
Blood chemistry analysis
Blood urea nitrogen 3.4 mg/dL
Creatinine 0.86 mg/dL
Sodium 145 mEq/L
Potassium 3.3 mEq/L
Chloride 108 mEq/L
Creatinine kinase 114 U/L
Aspartate aminotransferase 28 U/L
Alanine aminotransferase 25 U/L
Total billirubin 0.5 mg/dL
Plasma Glucose 93 mg/dL
Endocrine Data
Piruirary gland Adrenal grand
GH 0.038 ng/mL Cortisol 0.7 μg/dL
IGF-1 55 ng/mL PRA 0.2 mg/mL/hr
ACTH <0.1 pg/mL Aldosterone 53 ng.dL
LH <0.07 mμU/mL DHEA-S <5 ng/mL
FSH <0.30 mμU/mL Testosterone <0.04 ng/dL
ADH <0.8 pg/mL Thiroid
PRL 36.63 ng/mL FT3 1.2 pg/mL
TSH 7.395 μU/mL FT4 0.5 ng/dL
Figure 2. Change in serum potassium. He had hypokalemia at the time of admission, but he recovered spontaneously without treatment.
MRI revealed a pituitary tumor that the brain tumor was an intraceller component and pineal gland (Fig. 3), and a neurosurgeon performed an endoscopic biopsy of the tumor under local anesthesia. Later, his ECG showed a prolonged QT interval and ventricular (or atrial) bigeminy, and torsade de pointes (TdP) developed following single premature ventricular contractions (PVCs) in the short-long-short sequence. The patient lost consciousness during TdP, from which he recovered spontaneously (Fig. 4). Cardiac ultrasound performed immediately after TdP did not reveal any obvious abnormal wall movement, and acute coronary syndrome was denied. He was then diagnosed with biopsy-proven germinoma.
Figure 3. The sagittal magnetic resonance imaging of the brain showed the pituitary tumor (among white arrows).
Figure 4. The electrocardiogram monitor during surgical operation. The monitor showed prolonged QT interval and ventricular (or atrial) bigeminy, and a torsade de pointes (TdP) developed subsequent to single PVC on the short-long-short sequence. The blood pressure was fall down at the same time as TdP started.
The patient was prescribed carboplatin, etoposide, and hormone replacement therapy. At the six-month follow-up examination, his tumor had reduced in size; however, the panhypopituitarism persisted, and hormone replacement therapy was continued. The QTc interval had shortened from 519 to 418 ms (Fig. 5), and no more syncopal episodes were reported.
Figure 5. The corrected QT (QTc) interval improved from 519 ms on the admission to 418 ms after the chemotherapy. 1) On admission, 2) Just after TdP/Before Chemotherapy, 3) A few days after biopsy, 4) After the chemotherapy and the hormone replacement therapy.
Due to these results, the syncope was attributed to TdP due to prolonged LQTS caused by the brain tumor.
Discussion
The exact mechanism underlying QT interval prolongation is currently unknown. However, there have been several reports of hypopituitarism causing prolonged QT. There are three main hypotheses concerning how hypopituitarism might cause prolonged QT. First, cortisol deficiency has been shown to cause K-channel down-regulation, resulting in repolarization disorder and increasing a patient’s susceptibility to fatal arrhythmias, such as TdP (4). Second, cortisol deficiency results in down-regulation of calcium transporter, resulting in increased intracellular Ca concentration and leading to abnormalities in the repolarization process, which then manifests as a prolonged QT interval (5). Third, cortisol deficiency causes hypomagnesemia. Prolonged hypomagnesemia depletes intracellular K, resulting in hypokalemia (6).
One of the causes of acquired LQTS is a cerebrovascular disorder, such as subarachnoid hemorrhaging; however, QT prolongation due to a cerebrovascular disorder is induced by an autonomic imbalance and hyperactivity of the sympathetic nervous system coupled with increased intracranial pressure (7,8).
We speculate that germinoma may cause QT prolongation through panhypopituitarism, specifically hypothyroidism and decreased levels of adrenocorticotropic hormone (ACTH). After chemotherapy for germinoma and hormone replacement therapy for panhypopituitarism, the present patient had no recurrence of T-LOC despite taking no drugs, such as β-blockers or potassium supplementation.
This case report has two limitations. First, Takotsubo cardiomyopathy could not be completely ruled out because the electrocardiogram showed changes under stress. However, this diagnosis is unlikely because there was no chest pain, and no abnormal wall movements were seen on echocardiography. Second, we did not perform any investigations to check for genetic abnormalities. However, since there was no family history of sudden death, and hormone replacement therapy improved the ECG abnormalities, it is unlikely that QT prolongation was due to genetic abnormalities.
Conclusion
We herein report a man with a pituitary tumor who presented with QT elongation and chronic T-LOC. Brain tumors might cause QT prolongation through panhypopituitarism; patients with brain tumors presenting with T-LOC might therefore have cardiogenic syncope. Physicians should check the QTc interval of all patients presenting with T-LOC to rule out underlying conditions, such as panhypopituitarism.
The authors state that they have no Conflict of Interest (COI). | LEVETIRACETAM, VALPROATE SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33642483 | 19,997,413 | 2021-08-15 |
What was the administration route of drug 'LEVETIRACETAM'? | Polymorphic Ventricular Tachycardia with QT Interval Prolongation Due to a Brain Tumor.
We herein report the case of a 20-year-old man with a history of epilepsy who presented with frequent transient loss of consciousness (T-LOC) and polymorphic ventricular tachycardia (VT) with QT interval prolongation. Blood investigations revealed panhypopituitarism. Following a biopsy, he was diagnosed with brain germinoma. During the biopsy, he had an episode of polymorphous VT with QT prolongation. There was no recurrence of T-LOC following chemotherapy and hormone replacement therapy. This case indicates the importance of checking the QT interval in patients with T-LOC, including those with seizures and brain tumors, to ensure appropriate treatment.
pmcIntroduction
Long QT syndrome (LQTS) can be congenital or acquired. The causes of acquired LQTS are diverse, including drugs, metabolic and electrolyte abnormalities, heart disease, and central nervous system disorders. Electrolyte abnormalities include hypokalemia, hypomagnesemia, and hypocalcemia. Hypopituitarism might lead to electrolyte abnormalities, and there are several reports of loss of consciousness due to hypopituitarism (1-3).
We herein report a case of QT prolongation caused by electrolyte abnormalities associated with hypopituitarism due to a pituitary tumor.
Case Report
A 20-year-old man with a history of epilepsy was diagnosed with a brain tumor and referred to our neurosurgical department for treatment. He began to experience episodes of transient loss of consciousness (T-LOC) for 1 year and 3 months almost twice a week despite taking antiepileptic drugs (Sodium valproate 800 mg, and Levetiracetam 1,000 mg). These episodes occurred both at rest and during exercise. An electrocardiogram (ECG) abnormality had been noted in his records two years before the onset of T-LOC. A pituitary tumor was identified on magnetic resonance imaging (MRI), and he was subsequently referred to the neurosurgery department for a biopsy. He had no family history of sudden death or structural heart disease.
On admission, his ECG (Fig. 1) showed sinus rhythm with a heart rate of 60 beats per minute, and the corrected QT (QTc) interval was prolonged to 519 ms. An echocardiogram showed a normal ventricular function with no structural heart disease. Blood investigations (Table) revealed panhypopituitarism, including hypopituitarism, hypoadrenalism, and hypothyroidism. He had hypokalemia at the time of admission but recovered spontaneously without treatment (Fig. 2).
Figure 1. His electrocardiogram on admission showed sinus rhythm with a heart rate of 60 times, and the corrected QT interval prolonged to 519 ms. QRS complexes were without any abnormality.
Table. Patient's Laboratory Data.
Laboratory data on admission
Complete blood count
White blood cells 6,800 /μL
Red blood cells 380×10^4 /μL
Hemoglobin 11.8 g/dL
Platelets 109×10^3 /μL
Blood chemistry analysis
Blood urea nitrogen 3.4 mg/dL
Creatinine 0.86 mg/dL
Sodium 145 mEq/L
Potassium 3.3 mEq/L
Chloride 108 mEq/L
Creatinine kinase 114 U/L
Aspartate aminotransferase 28 U/L
Alanine aminotransferase 25 U/L
Total billirubin 0.5 mg/dL
Plasma Glucose 93 mg/dL
Endocrine Data
Piruirary gland Adrenal grand
GH 0.038 ng/mL Cortisol 0.7 μg/dL
IGF-1 55 ng/mL PRA 0.2 mg/mL/hr
ACTH <0.1 pg/mL Aldosterone 53 ng.dL
LH <0.07 mμU/mL DHEA-S <5 ng/mL
FSH <0.30 mμU/mL Testosterone <0.04 ng/dL
ADH <0.8 pg/mL Thiroid
PRL 36.63 ng/mL FT3 1.2 pg/mL
TSH 7.395 μU/mL FT4 0.5 ng/dL
Figure 2. Change in serum potassium. He had hypokalemia at the time of admission, but he recovered spontaneously without treatment.
MRI revealed a pituitary tumor that the brain tumor was an intraceller component and pineal gland (Fig. 3), and a neurosurgeon performed an endoscopic biopsy of the tumor under local anesthesia. Later, his ECG showed a prolonged QT interval and ventricular (or atrial) bigeminy, and torsade de pointes (TdP) developed following single premature ventricular contractions (PVCs) in the short-long-short sequence. The patient lost consciousness during TdP, from which he recovered spontaneously (Fig. 4). Cardiac ultrasound performed immediately after TdP did not reveal any obvious abnormal wall movement, and acute coronary syndrome was denied. He was then diagnosed with biopsy-proven germinoma.
Figure 3. The sagittal magnetic resonance imaging of the brain showed the pituitary tumor (among white arrows).
Figure 4. The electrocardiogram monitor during surgical operation. The monitor showed prolonged QT interval and ventricular (or atrial) bigeminy, and a torsade de pointes (TdP) developed subsequent to single PVC on the short-long-short sequence. The blood pressure was fall down at the same time as TdP started.
The patient was prescribed carboplatin, etoposide, and hormone replacement therapy. At the six-month follow-up examination, his tumor had reduced in size; however, the panhypopituitarism persisted, and hormone replacement therapy was continued. The QTc interval had shortened from 519 to 418 ms (Fig. 5), and no more syncopal episodes were reported.
Figure 5. The corrected QT (QTc) interval improved from 519 ms on the admission to 418 ms after the chemotherapy. 1) On admission, 2) Just after TdP/Before Chemotherapy, 3) A few days after biopsy, 4) After the chemotherapy and the hormone replacement therapy.
Due to these results, the syncope was attributed to TdP due to prolonged LQTS caused by the brain tumor.
Discussion
The exact mechanism underlying QT interval prolongation is currently unknown. However, there have been several reports of hypopituitarism causing prolonged QT. There are three main hypotheses concerning how hypopituitarism might cause prolonged QT. First, cortisol deficiency has been shown to cause K-channel down-regulation, resulting in repolarization disorder and increasing a patient’s susceptibility to fatal arrhythmias, such as TdP (4). Second, cortisol deficiency results in down-regulation of calcium transporter, resulting in increased intracellular Ca concentration and leading to abnormalities in the repolarization process, which then manifests as a prolonged QT interval (5). Third, cortisol deficiency causes hypomagnesemia. Prolonged hypomagnesemia depletes intracellular K, resulting in hypokalemia (6).
One of the causes of acquired LQTS is a cerebrovascular disorder, such as subarachnoid hemorrhaging; however, QT prolongation due to a cerebrovascular disorder is induced by an autonomic imbalance and hyperactivity of the sympathetic nervous system coupled with increased intracranial pressure (7,8).
We speculate that germinoma may cause QT prolongation through panhypopituitarism, specifically hypothyroidism and decreased levels of adrenocorticotropic hormone (ACTH). After chemotherapy for germinoma and hormone replacement therapy for panhypopituitarism, the present patient had no recurrence of T-LOC despite taking no drugs, such as β-blockers or potassium supplementation.
This case report has two limitations. First, Takotsubo cardiomyopathy could not be completely ruled out because the electrocardiogram showed changes under stress. However, this diagnosis is unlikely because there was no chest pain, and no abnormal wall movements were seen on echocardiography. Second, we did not perform any investigations to check for genetic abnormalities. However, since there was no family history of sudden death, and hormone replacement therapy improved the ECG abnormalities, it is unlikely that QT prolongation was due to genetic abnormalities.
Conclusion
We herein report a man with a pituitary tumor who presented with QT elongation and chronic T-LOC. Brain tumors might cause QT prolongation through panhypopituitarism; patients with brain tumors presenting with T-LOC might therefore have cardiogenic syncope. Physicians should check the QTc interval of all patients presenting with T-LOC to rule out underlying conditions, such as panhypopituitarism.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33642483 | 19,997,413 | 2021-08-15 |
What was the administration route of drug 'VALPROATE SODIUM'? | Polymorphic Ventricular Tachycardia with QT Interval Prolongation Due to a Brain Tumor.
We herein report the case of a 20-year-old man with a history of epilepsy who presented with frequent transient loss of consciousness (T-LOC) and polymorphic ventricular tachycardia (VT) with QT interval prolongation. Blood investigations revealed panhypopituitarism. Following a biopsy, he was diagnosed with brain germinoma. During the biopsy, he had an episode of polymorphous VT with QT prolongation. There was no recurrence of T-LOC following chemotherapy and hormone replacement therapy. This case indicates the importance of checking the QT interval in patients with T-LOC, including those with seizures and brain tumors, to ensure appropriate treatment.
pmcIntroduction
Long QT syndrome (LQTS) can be congenital or acquired. The causes of acquired LQTS are diverse, including drugs, metabolic and electrolyte abnormalities, heart disease, and central nervous system disorders. Electrolyte abnormalities include hypokalemia, hypomagnesemia, and hypocalcemia. Hypopituitarism might lead to electrolyte abnormalities, and there are several reports of loss of consciousness due to hypopituitarism (1-3).
We herein report a case of QT prolongation caused by electrolyte abnormalities associated with hypopituitarism due to a pituitary tumor.
Case Report
A 20-year-old man with a history of epilepsy was diagnosed with a brain tumor and referred to our neurosurgical department for treatment. He began to experience episodes of transient loss of consciousness (T-LOC) for 1 year and 3 months almost twice a week despite taking antiepileptic drugs (Sodium valproate 800 mg, and Levetiracetam 1,000 mg). These episodes occurred both at rest and during exercise. An electrocardiogram (ECG) abnormality had been noted in his records two years before the onset of T-LOC. A pituitary tumor was identified on magnetic resonance imaging (MRI), and he was subsequently referred to the neurosurgery department for a biopsy. He had no family history of sudden death or structural heart disease.
On admission, his ECG (Fig. 1) showed sinus rhythm with a heart rate of 60 beats per minute, and the corrected QT (QTc) interval was prolonged to 519 ms. An echocardiogram showed a normal ventricular function with no structural heart disease. Blood investigations (Table) revealed panhypopituitarism, including hypopituitarism, hypoadrenalism, and hypothyroidism. He had hypokalemia at the time of admission but recovered spontaneously without treatment (Fig. 2).
Figure 1. His electrocardiogram on admission showed sinus rhythm with a heart rate of 60 times, and the corrected QT interval prolonged to 519 ms. QRS complexes were without any abnormality.
Table. Patient's Laboratory Data.
Laboratory data on admission
Complete blood count
White blood cells 6,800 /μL
Red blood cells 380×10^4 /μL
Hemoglobin 11.8 g/dL
Platelets 109×10^3 /μL
Blood chemistry analysis
Blood urea nitrogen 3.4 mg/dL
Creatinine 0.86 mg/dL
Sodium 145 mEq/L
Potassium 3.3 mEq/L
Chloride 108 mEq/L
Creatinine kinase 114 U/L
Aspartate aminotransferase 28 U/L
Alanine aminotransferase 25 U/L
Total billirubin 0.5 mg/dL
Plasma Glucose 93 mg/dL
Endocrine Data
Piruirary gland Adrenal grand
GH 0.038 ng/mL Cortisol 0.7 μg/dL
IGF-1 55 ng/mL PRA 0.2 mg/mL/hr
ACTH <0.1 pg/mL Aldosterone 53 ng.dL
LH <0.07 mμU/mL DHEA-S <5 ng/mL
FSH <0.30 mμU/mL Testosterone <0.04 ng/dL
ADH <0.8 pg/mL Thiroid
PRL 36.63 ng/mL FT3 1.2 pg/mL
TSH 7.395 μU/mL FT4 0.5 ng/dL
Figure 2. Change in serum potassium. He had hypokalemia at the time of admission, but he recovered spontaneously without treatment.
MRI revealed a pituitary tumor that the brain tumor was an intraceller component and pineal gland (Fig. 3), and a neurosurgeon performed an endoscopic biopsy of the tumor under local anesthesia. Later, his ECG showed a prolonged QT interval and ventricular (or atrial) bigeminy, and torsade de pointes (TdP) developed following single premature ventricular contractions (PVCs) in the short-long-short sequence. The patient lost consciousness during TdP, from which he recovered spontaneously (Fig. 4). Cardiac ultrasound performed immediately after TdP did not reveal any obvious abnormal wall movement, and acute coronary syndrome was denied. He was then diagnosed with biopsy-proven germinoma.
Figure 3. The sagittal magnetic resonance imaging of the brain showed the pituitary tumor (among white arrows).
Figure 4. The electrocardiogram monitor during surgical operation. The monitor showed prolonged QT interval and ventricular (or atrial) bigeminy, and a torsade de pointes (TdP) developed subsequent to single PVC on the short-long-short sequence. The blood pressure was fall down at the same time as TdP started.
The patient was prescribed carboplatin, etoposide, and hormone replacement therapy. At the six-month follow-up examination, his tumor had reduced in size; however, the panhypopituitarism persisted, and hormone replacement therapy was continued. The QTc interval had shortened from 519 to 418 ms (Fig. 5), and no more syncopal episodes were reported.
Figure 5. The corrected QT (QTc) interval improved from 519 ms on the admission to 418 ms after the chemotherapy. 1) On admission, 2) Just after TdP/Before Chemotherapy, 3) A few days after biopsy, 4) After the chemotherapy and the hormone replacement therapy.
Due to these results, the syncope was attributed to TdP due to prolonged LQTS caused by the brain tumor.
Discussion
The exact mechanism underlying QT interval prolongation is currently unknown. However, there have been several reports of hypopituitarism causing prolonged QT. There are three main hypotheses concerning how hypopituitarism might cause prolonged QT. First, cortisol deficiency has been shown to cause K-channel down-regulation, resulting in repolarization disorder and increasing a patient’s susceptibility to fatal arrhythmias, such as TdP (4). Second, cortisol deficiency results in down-regulation of calcium transporter, resulting in increased intracellular Ca concentration and leading to abnormalities in the repolarization process, which then manifests as a prolonged QT interval (5). Third, cortisol deficiency causes hypomagnesemia. Prolonged hypomagnesemia depletes intracellular K, resulting in hypokalemia (6).
One of the causes of acquired LQTS is a cerebrovascular disorder, such as subarachnoid hemorrhaging; however, QT prolongation due to a cerebrovascular disorder is induced by an autonomic imbalance and hyperactivity of the sympathetic nervous system coupled with increased intracranial pressure (7,8).
We speculate that germinoma may cause QT prolongation through panhypopituitarism, specifically hypothyroidism and decreased levels of adrenocorticotropic hormone (ACTH). After chemotherapy for germinoma and hormone replacement therapy for panhypopituitarism, the present patient had no recurrence of T-LOC despite taking no drugs, such as β-blockers or potassium supplementation.
This case report has two limitations. First, Takotsubo cardiomyopathy could not be completely ruled out because the electrocardiogram showed changes under stress. However, this diagnosis is unlikely because there was no chest pain, and no abnormal wall movements were seen on echocardiography. Second, we did not perform any investigations to check for genetic abnormalities. However, since there was no family history of sudden death, and hormone replacement therapy improved the ECG abnormalities, it is unlikely that QT prolongation was due to genetic abnormalities.
Conclusion
We herein report a man with a pituitary tumor who presented with QT elongation and chronic T-LOC. Brain tumors might cause QT prolongation through panhypopituitarism; patients with brain tumors presenting with T-LOC might therefore have cardiogenic syncope. Physicians should check the QTc interval of all patients presenting with T-LOC to rule out underlying conditions, such as panhypopituitarism.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33642483 | 19,997,413 | 2021-08-15 |
What was the outcome of reaction 'Loss of consciousness'? | Polymorphic Ventricular Tachycardia with QT Interval Prolongation Due to a Brain Tumor.
We herein report the case of a 20-year-old man with a history of epilepsy who presented with frequent transient loss of consciousness (T-LOC) and polymorphic ventricular tachycardia (VT) with QT interval prolongation. Blood investigations revealed panhypopituitarism. Following a biopsy, he was diagnosed with brain germinoma. During the biopsy, he had an episode of polymorphous VT with QT prolongation. There was no recurrence of T-LOC following chemotherapy and hormone replacement therapy. This case indicates the importance of checking the QT interval in patients with T-LOC, including those with seizures and brain tumors, to ensure appropriate treatment.
pmcIntroduction
Long QT syndrome (LQTS) can be congenital or acquired. The causes of acquired LQTS are diverse, including drugs, metabolic and electrolyte abnormalities, heart disease, and central nervous system disorders. Electrolyte abnormalities include hypokalemia, hypomagnesemia, and hypocalcemia. Hypopituitarism might lead to electrolyte abnormalities, and there are several reports of loss of consciousness due to hypopituitarism (1-3).
We herein report a case of QT prolongation caused by electrolyte abnormalities associated with hypopituitarism due to a pituitary tumor.
Case Report
A 20-year-old man with a history of epilepsy was diagnosed with a brain tumor and referred to our neurosurgical department for treatment. He began to experience episodes of transient loss of consciousness (T-LOC) for 1 year and 3 months almost twice a week despite taking antiepileptic drugs (Sodium valproate 800 mg, and Levetiracetam 1,000 mg). These episodes occurred both at rest and during exercise. An electrocardiogram (ECG) abnormality had been noted in his records two years before the onset of T-LOC. A pituitary tumor was identified on magnetic resonance imaging (MRI), and he was subsequently referred to the neurosurgery department for a biopsy. He had no family history of sudden death or structural heart disease.
On admission, his ECG (Fig. 1) showed sinus rhythm with a heart rate of 60 beats per minute, and the corrected QT (QTc) interval was prolonged to 519 ms. An echocardiogram showed a normal ventricular function with no structural heart disease. Blood investigations (Table) revealed panhypopituitarism, including hypopituitarism, hypoadrenalism, and hypothyroidism. He had hypokalemia at the time of admission but recovered spontaneously without treatment (Fig. 2).
Figure 1. His electrocardiogram on admission showed sinus rhythm with a heart rate of 60 times, and the corrected QT interval prolonged to 519 ms. QRS complexes were without any abnormality.
Table. Patient's Laboratory Data.
Laboratory data on admission
Complete blood count
White blood cells 6,800 /μL
Red blood cells 380×10^4 /μL
Hemoglobin 11.8 g/dL
Platelets 109×10^3 /μL
Blood chemistry analysis
Blood urea nitrogen 3.4 mg/dL
Creatinine 0.86 mg/dL
Sodium 145 mEq/L
Potassium 3.3 mEq/L
Chloride 108 mEq/L
Creatinine kinase 114 U/L
Aspartate aminotransferase 28 U/L
Alanine aminotransferase 25 U/L
Total billirubin 0.5 mg/dL
Plasma Glucose 93 mg/dL
Endocrine Data
Piruirary gland Adrenal grand
GH 0.038 ng/mL Cortisol 0.7 μg/dL
IGF-1 55 ng/mL PRA 0.2 mg/mL/hr
ACTH <0.1 pg/mL Aldosterone 53 ng.dL
LH <0.07 mμU/mL DHEA-S <5 ng/mL
FSH <0.30 mμU/mL Testosterone <0.04 ng/dL
ADH <0.8 pg/mL Thiroid
PRL 36.63 ng/mL FT3 1.2 pg/mL
TSH 7.395 μU/mL FT4 0.5 ng/dL
Figure 2. Change in serum potassium. He had hypokalemia at the time of admission, but he recovered spontaneously without treatment.
MRI revealed a pituitary tumor that the brain tumor was an intraceller component and pineal gland (Fig. 3), and a neurosurgeon performed an endoscopic biopsy of the tumor under local anesthesia. Later, his ECG showed a prolonged QT interval and ventricular (or atrial) bigeminy, and torsade de pointes (TdP) developed following single premature ventricular contractions (PVCs) in the short-long-short sequence. The patient lost consciousness during TdP, from which he recovered spontaneously (Fig. 4). Cardiac ultrasound performed immediately after TdP did not reveal any obvious abnormal wall movement, and acute coronary syndrome was denied. He was then diagnosed with biopsy-proven germinoma.
Figure 3. The sagittal magnetic resonance imaging of the brain showed the pituitary tumor (among white arrows).
Figure 4. The electrocardiogram monitor during surgical operation. The monitor showed prolonged QT interval and ventricular (or atrial) bigeminy, and a torsade de pointes (TdP) developed subsequent to single PVC on the short-long-short sequence. The blood pressure was fall down at the same time as TdP started.
The patient was prescribed carboplatin, etoposide, and hormone replacement therapy. At the six-month follow-up examination, his tumor had reduced in size; however, the panhypopituitarism persisted, and hormone replacement therapy was continued. The QTc interval had shortened from 519 to 418 ms (Fig. 5), and no more syncopal episodes were reported.
Figure 5. The corrected QT (QTc) interval improved from 519 ms on the admission to 418 ms after the chemotherapy. 1) On admission, 2) Just after TdP/Before Chemotherapy, 3) A few days after biopsy, 4) After the chemotherapy and the hormone replacement therapy.
Due to these results, the syncope was attributed to TdP due to prolonged LQTS caused by the brain tumor.
Discussion
The exact mechanism underlying QT interval prolongation is currently unknown. However, there have been several reports of hypopituitarism causing prolonged QT. There are three main hypotheses concerning how hypopituitarism might cause prolonged QT. First, cortisol deficiency has been shown to cause K-channel down-regulation, resulting in repolarization disorder and increasing a patient’s susceptibility to fatal arrhythmias, such as TdP (4). Second, cortisol deficiency results in down-regulation of calcium transporter, resulting in increased intracellular Ca concentration and leading to abnormalities in the repolarization process, which then manifests as a prolonged QT interval (5). Third, cortisol deficiency causes hypomagnesemia. Prolonged hypomagnesemia depletes intracellular K, resulting in hypokalemia (6).
One of the causes of acquired LQTS is a cerebrovascular disorder, such as subarachnoid hemorrhaging; however, QT prolongation due to a cerebrovascular disorder is induced by an autonomic imbalance and hyperactivity of the sympathetic nervous system coupled with increased intracranial pressure (7,8).
We speculate that germinoma may cause QT prolongation through panhypopituitarism, specifically hypothyroidism and decreased levels of adrenocorticotropic hormone (ACTH). After chemotherapy for germinoma and hormone replacement therapy for panhypopituitarism, the present patient had no recurrence of T-LOC despite taking no drugs, such as β-blockers or potassium supplementation.
This case report has two limitations. First, Takotsubo cardiomyopathy could not be completely ruled out because the electrocardiogram showed changes under stress. However, this diagnosis is unlikely because there was no chest pain, and no abnormal wall movements were seen on echocardiography. Second, we did not perform any investigations to check for genetic abnormalities. However, since there was no family history of sudden death, and hormone replacement therapy improved the ECG abnormalities, it is unlikely that QT prolongation was due to genetic abnormalities.
Conclusion
We herein report a man with a pituitary tumor who presented with QT elongation and chronic T-LOC. Brain tumors might cause QT prolongation through panhypopituitarism; patients with brain tumors presenting with T-LOC might therefore have cardiogenic syncope. Physicians should check the QTc interval of all patients presenting with T-LOC to rule out underlying conditions, such as panhypopituitarism.
The authors state that they have no Conflict of Interest (COI). | Recovered | ReactionOutcome | CC BY-NC-ND | 33642483 | 19,997,413 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | FLUOROURACIL, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuropathy peripheral'. | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | FLUOROURACIL, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenia'. | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | FLUOROURACIL, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapeutic product effect incomplete'. | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | FLUOROURACIL, GEMCITABINE, GIMERACIL\OTERACIL\TEGAFUR, IRINOTECAN, LEUCOVORIN CALCIUM, OXALIPLATIN, PACLITAXEL | DrugsGivenReaction | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'. | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | FLUOROURACIL, IRINOTECAN, LEVOLEUCOVORIN CALCIUM, OXALIPLATIN | DrugsGivenReaction | CC BY-NC-ND | 33642489 | 20,034,993 | 2021-08-15 |
What was the administration route of drug 'FLUOROURACIL'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | Intravenous drip | DrugAdministrationRoute | CC BY-NC-ND | 33642489 | 20,034,993 | 2021-08-15 |
What was the administration route of drug 'GIMERACIL\OTERACIL\TEGAFUR'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
What was the administration route of drug 'IRINOTECAN'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | Intravenous drip | DrugAdministrationRoute | CC BY-NC-ND | 33642489 | 20,034,993 | 2021-08-15 |
What was the administration route of drug 'LEVOLEUCOVORIN CALCIUM'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | Intravenous drip | DrugAdministrationRoute | CC BY-NC-ND | 33642489 | 20,034,993 | 2021-08-15 |
What was the administration route of drug 'OXALIPLATIN'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | Intravenous drip | DrugAdministrationRoute | CC BY-NC-ND | 33642489 | 20,034,993 | 2021-08-15 |
What was the dosage of drug 'GEMCITABINE'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | 1000 MILLIGRAM/SQ. METER, ON DAY 1, 8, 15, EVERY 4 WEEKS | DrugDosageText | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
What was the dosage of drug 'GIMERACIL\OTERACIL\TEGAFUR'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | 100 MILLIGRAM, DAILY | DrugDosageText | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
What was the dosage of drug 'LEUCOVORIN CALCIUM'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | 300 MILLIGRAM/SQ. METER | DrugDosageText | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
What was the dosage of drug 'LEUCOVORIN'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | 300 MG/M2, CYCLIC(EVERY 2 WEEKS) | DrugDosageText | CC BY-NC-ND | 33642489 | 20,572,580 | 2021-08-15 |
What was the dosage of drug 'LEVOLEUCOVORIN CALCIUM'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | 300 MG/M2 ONCE IN 2WEEKS | DrugDosageText | CC BY-NC-ND | 33642489 | 20,034,993 | 2021-08-15 |
What was the dosage of drug 'PACLITAXEL'? | Multiple-line Chemotherapy for a Patient with Unresectable Mucinous Cystic Neoplasm of the Pancreas.
A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFIRINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.
pmcIntroduction
Mucinous cystic neoplasms (MCNs) are rare disease, representing about 20% of all resected pancreatic cysts, and are known to occur in the pancreatic body and tail in women (1,2). Although MCNs are considered to have malignant potential, unresectable cases due to metastases or local invasion have rarely been reported. Palliative chemotherapy has been recommended for unresectable MCN in some reports (3,4); however, no clinical evidence has been established about the efficacy of such treatment.
In recent years, the efficacy of palliative chemotherapy for metastatic pancreatic ductal adenocarcinoma (PDAC) has evolved. Combination regimens, such as FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP), have been reported to achieve a high response rates and an improved overall survival (5,6). However, there are few reports on the efficacy of these combined chemotherapy regimens in unresectable MCN (7).
We herein report a patient with unresectable MCN who achieved a long-term survival under multi-line chemotherapy.
Case Report
A 74-year-old woman with a cystic lesion in her abdominal cavity was referred to the Yokohama City University Medical Center. During the physical examination, a soft, fist-sized mass was palpable in her left upper abdomen. Her serum tumor marker levels were normal (carcinoembryonic antigen: 3.6 ng/mL and carbohydrate antigen 19-9: 29 U/mL). Contrast-enhanced computed tomography (CECT) showed a cystic lesion of 9 cm in diameter with enhanced irregular wall thickening in the pancreatic tail (Fig. 1). There were enlarged lymph nodes along the hepatic artery (No. 12a) and on the anterior surface of the pancreas (No. 17). Ascites and tiny nodules around the mesentery were also observed. Contrast-enhanced transabdominal ultrasonography showed an enhanced septum inside the cyst (Fig. 2). Endoscopic ultrasonography did not reveal a connection between the cyst and the main pancreatic duct. Ascites cytology revealed an adenocarcinoma (Fig. 3); therefore, we made a diagnosis of MCN with an associated invasive carcinoma with peritoneal dissemination and lymph node metastases. We considered palliative chemotherapy to be the best option for the patient.
Figure 1. A 74-year-old woman with a mucinous cystic neoplasm of the pancreas. Contrast-enhanced computed tomography shows a 9-cm cystic lesion in the pancreas tail. Wall thickening is visible at the right side of the cyst (arrow). Swollen lymph nodes can be observed along the hepatic artery (black arrowhead) and in front of the pancreatic body (white arrowhead). Ascites is present around the liver and spleen.
Figure 2. A) Conventional transabdominal ultrasound shows a cystic lesion with wall thickening and hyperechoic content. B) Contrast-enhanced transabdominal ultrasonography reveals an enhanced septum inside the cyst (arrows). The thickened wall shows blood flow (arrowheads).
Figure 3. Ascites cytology shows adenocarcinoma containing mucus-like structures in the cytoplasm (arrows).
First-line chemotherapy consisting of 1,000 mg/m2 gemcitabine (GEM) on day 1, 8, and 15 every 4 weeks was started. At the beginning of treatment, the patient's performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) was Grade 0. After 3.9 months, CECT showed enlarged lymph nodes, indicating progressive disease (PD) based on the Response Evaluation Criteria in Solid Tumors (RECIST). The regimen was changed to 100 mg/day of S-1, an oral fluoropyrimidine, for 2 weeks, followed by a 1-week washout period. All adverse events were graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. The patient suffered from nausea and fatigue (Grade 2). After 6.6 months, the lymph nodes were again enlarged on CECT. Regarding GEM and S-1 monotherapy, the best effect of chemotherapy achieved was stable disease (SD), and the progression-free survival was 3.9 and 6.6 months, while the average relative dose intensity (ARDI) was 100% and 88%, respectively.
Subsequently, third-line chemotherapy was administered with 125 mg/m2 of nab-paclitaxel plus 1,000 mg/m2 of GEM on day 1, 8, and 15 repeated every 4 weeks. Because of neutropenia (Grade 3), the dose of both nab-paclitaxel and GEM was reduced to 60% of the initial dose, and the administration schedule was extended to biweekly. After 7.6 months, CECT showed significant improvement of the wall thickening of the cyst, shrinkage of the lymph nodes, and disappearance of ascites, which were considered to reflect a partial response (PR). GnP was continued for 20 cycles until PD was diagnosed based on exacerbation of the wall thickening of the cyst. The progression free survival (PFS) was 12.1 months, and the ARDI was 40%.
Since the patient's general condition was good at an ECOG-PS of 0, we selected modified FOLFIRINOX as the regimen for fourth-line chemotherapy, consisting of 65 mg/m2 of oxaliplatin, 120 mg/m2 of irinotecan, and 300 mg/m2 of leucovorin, followed by a continuous infusion of 2,400 mg/m2 of 5-FU over a 46-hour period, every 2 weeks. The dosage of oxaliplatin and irinotecan was reduced to 80% of the initial dose because of the elderly age of the patient. She experienced fatigue and peripheral sensory neuropathy, assessed as Grade 2, until cycle 2. Both oxaliplatin and irinotecan were reduced to 60% of the initial dose by the ninth cycle. After 1.9 months (3 cycles), a PR was achieved with remarkable shrinkage of the lymph nodes and improvement of wall thickening of the cyst. Modified FOLFIRINOX was continued with treatment interruption for three months and one month because of heart failure (Grade 3) and herpes zoster (Grade 2), respectively. After 20 cycles, CECT showed progression of the wall thickening of the cyst and enlargement of the lymph nodes, which were considered to reflect PD. The PFS under modified FOLFIRINOX was the longest among all regimens at 20.1 months. The ARDI of the 3 drugs - oxaliplatin, irinotecan, and 5-FU - was 35% (Fig. 4).
Figure 4. Sequential computed tomography images obtained over 2.5 years during combined chemotherapy of a mucinous cystic neoplasm of the pancreas. A, B, C) At the start of nab-paclitaxel plus gemcitabine as third-line chemotherapy, the lymph nodes along the hilar artery (black arrowhead) and anterior portion of the pancreas (white arrowhead) and wall thickening of the cyst (arrows) are shown. D, E, F) A partial response is achieved after six cycles (seven months) of nab-paclitaxel plus gemcitabine with the findings of lymph nodes shrinkage. G, H, I) After 20 cycles (13 months), enlargement of the lymph nodes along the hilar artery (black arrowheads) and wall thickening (arrows) confirm progressive disease. J, K, L) A partial response is visible after three cycles (two months) of modified FOLFIRINOX. M, N, O) After 20 cycles (20.4 month), the enlargement of the lymph nodes along the hilar artery (black arrowheads) demonstrates progressive disease.
We suggested the patient finish palliative chemotherapy; however, she strongly preferred to continue anti-cancer therapy. Therefore, fifth-line chemotherapy with 1,000 mg/m2 of GEM on day 1 and 80 mg/day of S-1 from day 1 to 7 was administered every 3 weeks, and the PFS was 5.1 months. After 9.4 months, best supportive care was provided, but the ascites increased, and her general condition deteriorated to ECOG PS 2.
Another seven months later, the patient was hospitalized for one week due to an infection inside the cyst, but conservative therapy with antibiotics was effective in resolving this. Eventually, she died as a consequence of the primary tumor after 14.1 months of best supportive care. The overall survival from the beginning of first-line chemotherapy was 69.4 months, including 55.2 months receiving palliative chemotherapy (Table) (Fig. 5).
Table. Results of Systematic Chemotherapy.
Regimen Best Response PFS ARDI
1st line Gemcitabine SD 3.9 months 100%
2nd line S-1 SD 6.6 months 88%
3rd line Nab-paclitaxel plus Gemcitabine PR 12.1 months 40%
4th line Modified-FOLFIRINOX PR 20.4 months 35%
5th line Gemcitabine plus S-1 SD 5.1 months 44%
Effect of chemotherapy was evaluated by RECIST guideline. FOLFIRINOX is consist of oxaliplatin, irinotecan, 5-FU, and leucovorin. RECIST: response evaluation criteria in solid tumors, PFS: progression free survival, ARDI: average relative dose intensity, PR: partial response, SD: stable disease
Figure 5. Clinical course with changes in tumor markers and transition for each regimen. GEM: gemcitabine, GnP: nab-paclitaxel plus gemcitabine, mFFX: Modified-FOLFIRINOX, GS: gemcitabine plus S-1
Discussion
MCN of the pancreas is a rare tumor that occurs predominantly in middle-aged women (8). When diagnosing MCN, it is important to differentiate it from branched-type intraductal papillary mucinous neoplasm (IPMN) (9). MCN is histologically diagnosed based on the existence of an ovarian-type stroma (10,11). If a surgical specimen is not available, the clinical diagnosis is made based on the characteristics of a unilocular or septated macrocystic lesion without connection to the pancreatic duct, enhancing mural nodules on CECT, and wall thickening (12,13). A cytological analysis after endoscopic ultrasound-guided fine-needle aspiration can detect malignant cystic lesions. However, it is difficult to differentiate between IPMN and MCN with a small specimen (14). We did not aspirate any contents of the cyst; however, the cytology of the patient's ascites revealed an adenocarcinoma. In the present case, the diagnosis of MCN was confirmed by the characteristics of a cyst with irregular wall thickening and no connection to the main pancreatic duct.
Although MCN is considered to have malignant potential, there are only a few reports describing the rate of malignancy. Postlewait et al. (2), reported that 14.9% of 349 patients with resected pancreatic MCN had adenocarcinoma or high-grade dysplasia. Among them, lymph node metastasis was observed in about one-third. Due to this low incidence of metastasis, the prognosis of malignant MCN was better than that of PDAC, with a 3-year survival rate of 59%. However, regarding unresectable MCN, the prognosis is significantly worse than that of surgically treated cases (8,15,16).
Although palliative chemotherapy is recommended for unresectable or recurrent cystic lesions of the pancreas (14), there is currently no evidence guiding the best choice of regimen for unresectable MCN. Werner et al. (4). reported 5 patients who received palliative chemotherapy for unresectable MCN and observed a median survival time of 11 months (range: 4-37 months). In that report, GEM-based treatment had been selected in accordance with the recommended palliative chemotherapy of PDAC. However, the outcomes of chemotherapy for PDAC have radically improved with the advent of two regimens: FOLFIRINOX and GnP (5,6). These combined chemotherapies have resulted in remarkable increases in the survival compared with GEM alone in patients with metastatic PDAC. However, these regimens also increase the frequency of severe adverse events; therefore, they are not recommended for use in patients with a poor general condition or an old age. At the time of initiating treatment for the present patient, GnP was not yet covered by national health insurance in Japan, and we did not have adequate experience regarding the clinical use of FOLFIRINOX. In addition, there were no reports concerning the use of GnP or FOLFIRINOX for MCN at the time. Therefore, we selected a less toxic monotherapy of GEM or S-1 as the first and second regimens. However, neither of these monotherapies achieved tumor shrinkage, so we switched to more toxic regimens.
Although FOLFIRINOX and GnP have been reported to be highly toxic, we were able to administer both of them to our patient for long periods of time at reduced dosages. For GnP, we reduced the dosage and frequency because of neutropenia (Grade 3) in the fourth cycle. However, after the fifth cycle, no severe adverse events were observed. The ARDI of GnP was lower than the values noted in previous reports (6,17); however, our patient was able to continue treatment for up to 12.1 months while maintaining a good PS. Brunetti et al. (7) reported the overall survival time of patients with unresectable MCN treated with GnP and FOLFIRINOX as 13 months and 9-14 months, respectively. Among these patients, 2 received both regimens, and their overall survival times were 9 and 14 months, respectively. Compared with these cases, the present case achieved a long survival.
Despite the fact that our patient has already received GEM monotherapy, GnP achieved PR, with the antitumor effect lasting for one year. This result may be due to the fact that nab-paclitaxel increases intratumoral GEM levels. Frese et al. (18) reported that paclitaxel reduced the levels of cytidine deaminase protein, which is associated with the metabolization of GEM, in mice. This synergistic effect may be the reason for the tumor reduction under GnP, although the ARDI was as low as 40%.
It may be considered controversial to administer modified FOLFIRINOX as the fourth-line chemotherapy because the patient was 76 years old at the time. Furthermore, there were no clinical reports that modified FOLFIRINOX was effective in patients with unresectable MCN. However, the patient's good general condition (ECOG-PS 0) and her strong preference supported the decision to choose modified FOLFIRINOX. After three cycles, the thickness of the cyst wall had remarkably regressed on CECT, and the regimen was continued with intermissions for 20 cycles. Modified FOLFIRINOX had to be stopped because of heart failure (Grade 3) for 3 months after 8 cycles and because of herpes zoster (Grade 2) for 1 month after 10 cycles. However, we were able to restart the same regimen with dose reductions.
Several studies investigated the efficacy of modified FOLFIRINOX in patients with GEM-refractory PDAC (19-21). Sawada et al. reported the efficacy and good tolerability of modified FOLFIRINOX as second-line therapy after GnP (22). Although FOLFIRINOX poses a risk of serious adverse events, these studies have shown that it can be safely administered when doses are reduced. In this case, both oxaliplatin and irinotecan were first reduced to 80% of the initial dose and ultimately to 60%. Considering the interruptions in the administration, the ARDI reached 35%. Nevertheless, modified FOLFIRINOX was continued without tumor progression for 20.4 months. Peripheral neuropathy is the most important adverse event associated with the crossover therapy of GnP and modified FOLFIRINOX. Our patient suffered Grade 2 peripheral neuropathy in the course of modified FOLFIRINOX that did not require treatment interruption.
In conclusion, unresectable MCN is rare, and there is little clinical evidence supporting its treatment with combined chemotherapy. In our patient, only GnP and modified FOLFIRINOX achieved PR among the five regimens used. Although further large-scale prospective studies are required to confirm the efficacy and feasibility in patients with unresectable MCN, we recommend GnP and modified FOLFIRINOX to prolong the survival under palliative chemotherapy.
The authors state that they have no Conflict of Interest (COI). | 125 MILLIGRAM/SQ. METER, ON DAY 1, 8, 15, EVERY 4 WEEKS | DrugDosageText | CC BY-NC-ND | 33642489 | 20,980,647 | 2021-08-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Enterocolitis'. | Rituximab-induced Ileocolitis in a Patient with Gastric MALToma: A Case Report and Literature Review.
Rituximab (RTX) is effective for treating cancer, but reports of RTX-associated enterocolitis are limited. We herein report the case of a 65-year-old man who developed RTX-induced ileocolitis. He was diagnosed with gastric mucosa-associated lymphoid tissue lymphoma (MALToma) and treated with RTX. He complained of bloody diarrhea after RTX. Mucosal inflammation on colonoscopy indicated RTX-induced ileocolitis. He was treated with corticosteroids, and his symptoms improved. We reviewed the RTX-associated gastrointestinal adverse events and classified the features into ulcerative colitis, Crohn's disease, microscopic colitis, and ileocolitis. To our knowledge, this is the first case of a Japanese patient who developed RTX-induced ileocolitis.
Introduction
Rituximab (RTX), the anti-cluster of differentiation (CD)20 chimeric antibody, depletes both CD19-positive and CD20-positive B cells via various mechanisms (1). This B-cell depletion therapy is effective for treating CD20-positive hematological malignancies, including mucosa-associated lymphoid tissue lymphoma (MALToma), non-Hodgkin lymphoma, and chronic lymphocytic leukemia (2); as well as autoimmune disorders, including rheumatoid arthritis, multiple sclerosis, and nephrotic syndrome.
Gastric lymphomas are classified into mainly MALToma and diffuse large B cell lymphoma, accounting for over 95% of cases, with others including follicular lymphoma, Mantle lymphoma, etc. Among MALTomas, gastric MALToma is primarily induced by Helicobactor pylori infection. Therefore, the first-line therapy is H. pylori eradication (3). When first-line therapy fails, chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and/or RTX are considered as second- or third-line therapy in advanced cases. In addition, radiation therapy is also considered for low-grade primary gastric MALToma.
RTX is well-tolerated in most cases. However, relatively rare and late-onset adverse events have been reported, including gastrointestinal tract issues (4,5). Among patients who received RTX and underwent colonoscopy, 4% were reported to develop RTX-associated colitis (4).
A diagnosis of biologics-induced enterocolitis is based on clinical manifestations, the endoscopic appearance, and histological features. The endoscopic features of immunosuppressive agent-induced enterocolitis have been reported to include ulcerative colitis (UC) (6) and Crohn's disease (7). Microscopic colitis (MC) (8) and ileocolitis induced by RTX (9) have also been reported. To date, only 35 cases of RTX-associated enterocolitis have been reported.
To our knowledge, this is the first reported case of a Japanese man who received RTX for gastric MALToma, developed ileocolitis, and was successfully treated with corticosteroids (CSs).
Case Report
A 65-year-old man was referred to the Department of Gastroenterology at our hospital complaining of bloody diarrhea after RTX therapy for gastric MALToma.
Related medical history and presentation of current illness
He had a history of gastric ulcer with H. pylori infection, which was treated with the standard triple eradication regimen (amoxicillin/clarithromycin/lansoprazole).
He was diagnosed with gastric MALToma following a histological examination of the biopsy specimens from the antral gastric ulcer 4 years after H. pylori eradication. He was admitted to the hematology unit at our hospital. Bone marrow aspiration revealed no lymphoma cells. He was diagnosed with stage IV lymphoma under both the Ann Arbor classification and Lugano International classification due to metastasis in the cervical, subclavian, and mesenteric lymph nodes, as evaluated by computed tomography (CT), abdominal ultrasound, magnetic resonance imaging, and positron emission tomography (PET)-CT.
He was treated with four courses of RTX monotherapy with subsequent treatment of yttrium-conjugated ibritumomab tiuxetan (genetic recombination) and exhibited a partial response (PR). However, four months after the PR, follow-up PET-CT indicated the recurrence of lymphoma in the right cervical lymph nodes. He was treated with another four courses of RTX as the second-line therapy, which resulted in a complete response as evaluated by enhanced CT (data not shown). He complained of watery diarrhea occurring 20 times/day and bloody stool 2 days after the commencement of the second-line RTX therapy. No disease-related family history was reported.
Physical examination findings
A physical examination revealed no anemia, superficial lymph node swelling, or abdominal abnormalities.
Laboratory examination findings
The laboratory examination findings are presented in Table. A blood examination revealed leukocytosis (white blood cell count of 10,680/μL), mild anemia (Hb, 12.3 g/dL), hypersensitive C-reactive protein (CRP) (1.2 mg/L), a high erythrocyte sedimentation rate (ESR) (36 mm/h), cytomegalovirus (CMV) negativity, and human immunodeficiency virus (HIV) negativity. Biochemistry demonstrated no abnormality. His serum interleukin (IL)-2 level was 962 U/mL. The fecal occult blood test was positive. In addition, the fecal culture detected no significant microbiome (bacteria: negative).
Table. Laboratory Examination Findings.
Peripheral blood Biochemistry Hormone and tumor markers Viral antibodies
WBC 10,680 U/µL TP 7.3 g/dL TSH 1.16 µIU/mL CMV-Ag negative
neutrophils 67.8 % Alb 4.2 g/dL free T3 2.24 pg/mL HIV negative
lymphocytes 20.0 % AST 13 U/L free T4 1.18 pg/mL
monocytes 12.1 % ALT 10 U/L sIL-2R 962 U/mL
eosinophils 0.0 % LDH 128 U/L
basophils 0.1 % Cr 0.63 mg/dL
RBC 467 U/µL BUN 5.9 mg/dL
Hb 12.3 g/dL Na 138 mEq/L
Plt 25.7 U/µL Cl 98 mEq/L
ESR 36 mm/h K 3.9 mEq/L
CRP 1.2 mg/dL
WBC: white blood cell count, RBC: red blood cell count, Plt: platelets, ESR: erythrocyte sedimentation rate, TP: total protein, Alb: albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, LDH: lactate dehydrogenase, Cr: chromium, BUN: blood urea nitrogen, Na: sodium, Cl: chlorine, K: potassium, CRP: C-reactive protein, TSH: thyroid-stimulating hormone, sIL-2R: soluble form of interleukin 2 receptor, CMV: cytomegalovirus, HIV: human immunodeficiency virus
Imaging and endoscopic examination findings
Contrast enhanced-CT revealed consecutive circumferential hypertrophy in the terminal ileum through the rectum (Fig. 1). Reddish changes with multiple erosions in gastric antrum were observed by esophagogastroduodenoscopy (EGD) in January 201X before RTX monotherapy with subsequent treatment of yttrium-conjugated ibritumomab tiuxetan treatment (Fig. 2A). A pathological examination with biopsy specimens from the gastric antrum revealed MALToma. EGD revealed atrophic gastritis after H. pylori eradication, whereas ileocolonoscopy (ICS) revealed mild reddish mucosa in the terminal ileum (Fig. 2B), which differed from diffuse consecutive backwash ileitis as occasionally observed in severe UC. ICS showed scattered aphtha and diffuse consecutive inflammation throughout the transverse colon with normal mucosa in some regions (Fig. 2C). In addition, ICS revealed severe erosion and diffuse consecutive inflammation throughout the sigmoid colon and rectum (Fig. 2D).
Figure 1. A, B: Contrast-enhanced computed tomography revealed continuous circumferential hypertrophy from the terminal ileum to the rectum.
Figure 2. Esophagogastroduodenoscopy (EGD) and ileocolonoscopy findings. A: Reddish changes with multiple erosions in the gastric antrum in January 201X before R-CHOP treatment. B: Ileocolonoscopy (ICS) revealed mild reddish mucosa in the terminal ileum. C: ICS revealed scattered aphtha and diffuse consecutive inflammation throughout the transverse colon. D: ICS revealed severe erosion and diffuse consecutive inflammation throughout the sigmoid colon and rectum.
Histological examination findings
Hematoxylin and Eosin (H&E) staining of specimens from the colonic mucosa revealed that plasma cells were dominant in this segment (Fig. 3A), which was consistent with descriptions of RTX-induced colitis in the literature (10).
Figure 3. Histopathological and immunohistochemical findings in colonic mucosa specimens (before treatment) (×100). A: Hematoxylin and Eosin staining of the specimens from the colonic mucosa exhibited diffuse and circumferential erosions, epithelial atrophy, goblet cell reduction, and extensive intestinal inflammation. Furthermore, cryptitis and crypt abscess but not granuloma were observed in the colonic mucosa. B: Immunohistochemistry demonstrated increased CD3+ lymphocytes. C: The complete depletion of CD20+ lymphocytes in the colonic mucosa was demonstrated.
H&E staining of the colorectal mucosa demonstrated diffuse and circumferential erosions, epithelial atrophy, goblet cell reduction, and extensive intestinal inflammation. Furthermore, cryptitis and crypt abscess, but not granuloma, were observed in the colonic mucosa. Cytomegalovirus and pathogenic bacteria were not detected in biopsy specimens. In addition, the ileal erosion specimens indicated lymphocyte infiltration, and these lymphocytes had little atypia (data not shown). Although the presence of a thickened subepithelial collagen band and marked increase in intraepithelial lymphocytes (IELs) were not evaluated, microscopic colitis (MC) was denied, as MC shows endoscopically normal mucosa, in contrast to the present findings.
Immunohistochemistry demonstrated increased CD3-positive lymphocytes and complete depletion of CD20-positive lymphocytes in the colonic mucosa (Fig. 3B, C). In addition, specimens from the ileal erosions revealed CD3+T lymphocytes>CD79alpha+B lymphocytes infiltration. Furthermore, κ and λ chains were equivalent, suggesting no residual MALToma cells.
Differential diagnoses
Crohn's disease, Behçet's disease (BD), non-steroidal anti-inflammatory drug (NSAID)-induced ulcers, and infectious colitis, including bacterial, tuberculosis, and viral colitis, were considered as differential diagnoses.
The final diagnosis
Crohn's disease was excluded due to the absence of longitudinal ulcers or a cobblestone appearance. BD was excluded because no typical round ulcers were observed in the terminal ileum, and the BD diagnostic criteria were not met. The patient had no recent history of NSAID intake. The diagnosis of RTX-induced ileocolitis in the presented patient was thus confirmed based on the clinical, radiological, endoscopic, and histological criteria.
Treatment
The patient was treated with CSs (prednisolone) at a dose of 50 mg/day for 2 weeks. Subsequently CSs were tapered by 5 mg/2-3 weeks (Fig. 4).
Figure 4. Clinical findings. The clinical findings indicate that corticosteroid therapy was effective in ameliorating diarrhea and reducing inflammatory markers. PSL: prednisolone
Outcome and follow-up
The reported bloody diarrhea gradually improved despite CS tapering, and the symptoms had completely disappeared by three months' treatment with CSs. The mucosal and submucosal inflammation (Fig. 5) after additive CS treatment for two months had improved by five months after the start of CS therapy (Fig. 6). At the time of writing, gastric MALToma had not recurred. However, the swelling cervical lymph node was biopsied to reveal the CD30-positive, CD15-positive, pax-5-positive, and EBER-positive lymphoma. The patient was diagnosed with Hodgkin's lymphoma. Two cycles of an ABVD regimen and three cycles of Brentuximab vedotin therapy were administered, and complete remission was achieved. No recurrence had been observed at the time of writing this report.
Figure 5. Endoscopy findings. The endoscopic appearance of mucosal inflammation improved after 5-month corticosteroid treatment. A: Ascending colon, B: transverse colon, C: sigmoid colon, and D: rectum.
Figure 6. Histopathological and immunohistochemical findings (after treatment) (×100). A: Hematoxylin and Eosin staining of the colonic specimens after additive corticosteroid treatment demonstrated a significant reduction in the number of infiltrating inflammatory cells. B: Immunohistochemistry for CD3+ cells indicated a reduction in the infiltration of T cells. C: Immunohistochemistry for CD20+ cells demonstrated the recovery of the scattered infiltration of B cells in colonic mucosa.
Discussion
We herein report the case of a Japanese man who presented with RTX-induced ileocolitis. The patient had been treated for gastric MALToma with four courses of RTX monotherapy with subsequent treatment of yttrium-conjugated ibritumomab tiuxetan (genetic recombination) and exhibited a partial response because the swelling of the right cervical lymph nodes remained, which was indicated by follow-up PET-CT. He was treated with an additional four courses of RTX as third-line therapy, which resulted in a complete response. Thereafter he presented with severe watery diarrhea approximately five months (five doses) after the commencement of the first round of RTX with yttrium-conjugated ibritumomab tiuxetan therapy. The median period and median doses of RTX administered between the first RTX exposure and onset of diarrhea has been reported to be 8 months (4.5-29 months) and 6 doses (5-12 doses), respectively (8); therefore, the median time and administered doses in our case were consistent with those reported previously.
Our patient was 65 years old at the diagnosis. Eckmann et al. reported that the median age of patients diagnosed with inflammatory bowel disease (IBD) after RTX was 52.5 years old (8), which is older than the susceptible age of IBD in the general population, suggesting that the pathogenesis of RTX-associated colitis differs from that of IBD.
Colonoscopy demonstrated moderate-to-severe ileitis and pancolitis. His ileitis resembled Crohn's disease in terms of scattered erosions, and the colitis was similar to UC in terms of the diffuse consecutive circumferential inflammation from the cecum to the rectum. However, no longitudinal ulcers, cobblestone appearance, or skip lesions were observed in the intestine. In addition, the colitis in our patient differed from typical UC in that there was sparse visible vasculature throughout the colon and rectum. Furthermore, the surface appearance of the inflammatory colonic mucosa in this patient indicated the aggregation of small granules. However, small white hues representing cryptitis or crypt abscess are typical findings in UC. Therefore, there is a discrepancy in the mucosal appearance between this patient and typical UC patients. Colonoscopy revealed no punched-out ulcers in the terminal ileum or aphthoid lesions in the colon. Taken together, the colonoscopy findings indicated that our patient did not exhibit typical Crohn's disease, UC, or BD features.
A histological examination of the colonic biopsy specimens demonstrated epithelial atrophy and inflammatory cell infiltration composed of lymphocytes and plasma cells in the epithelium and lamina propria in the focal area. Immunohistochemistry revealed that these infiltrated cells were primarily CD3-positive T cells. CD20-positive B cells were depleted both immediately after RTX treatment and five months after treatment. Ardelean et al. reported a case of RTX-induced severe UC with the infiltration of mature CD3 T cells, cytotoxic CD8 T cells, and forkhead box P3 gene+ regulatory T cells, suggesting that their case was an adverse effect of RTX (11). This evaluation might confirm that the inflammation in the terminal ileum and colon in our case was also an adverse effect of RTX. Although the CD68+ histiocytes and CD68+ small granuloma in the lamina propria suggest the diagnosis of Crohn's disease (7), this finding is not specific to Crohn's disease. In addition, no multinucleate giant cell granuloma, which is typically observed in Crohn's disease, was found in our case. CMV was negative in the biopsy specimens.
Eckmann et al. reported nine cases of MC induced by RTX (8). Collagenous colitis and lymphocytic colitis are included in MC. However, collagen bands in the submucosa and an increase in intraepithelial lymphocytes were not observed in our case, suggesting this was not a case of MC.
With regard to the diagnosis, infectious enterocolitis, including bacterial, viral, and tuberculosis, and the recurrence of MALToma were excluded based on the findings of culture and a histopathological examination. Although yttrium-conjugated ibritumomab tiuxetan might induce or affect ileocolitis, no case of yttrium-conjugated ibritumomab tiuxetan-induced ileocolitis has been reported. Given the present findings, we diagnosed the patient with RTX-induced T cell-mediated ileocolitis.
RTX therapy induced complete depletion of both peripheral and intestinal CD19+ and CD20+ B cells (12). Thereafter, the patient may have developed T cell-mediated intestinal inflammation manifesting as ileocolitis. RTX reportedly exacerbates UC, and B cells can modulate T cell proliferation or activation and induce anti-inflammatory effects via B cell-T cell interaction, as demonstrated by the recovery of mucosal regulatory T cells with the adaptive transfer technique in B cells (13). In our case, the complete depletion of B cells might have caused the downregulation of regulatory cytokines, such as IL-4, transforming growth factor-beta secreted from B cells in gut-associated lymphoid tissue and leading to the upregulation of inflammatory cytokines by activated T cells.
A total of 35 cases of UC, Crohn's disease, MC, and ileocolitis induced by RTX have been reported. Thirteen patients had RTX-induced UC (6,8,11,14), 11 had RTX-induced Crohn's disease (7,8,15,16), 9 had RTX-induced MC, and patients had ileocolitis (9), including our case.
The reason why different RTX-induced diseases (i.e., UC, Crohn's disease, MC, and ileocolitis) present in different patients has not been clarified. However, the loss of B cells might have caused cellular immune dysregulation, followed by the activation of cytotoxic T cells. Indeed, the association of RTX and ileocolitis or enterocolitis was suggested in one study demonstrating the development of severe colitis in B-cell-depleted double-knockout mice (17). In addition, one of the immunosuppressive roles of B cells is the control of pathogenic CD4+ T cells via the production of the regulatory cytokine IL-10 (10,17) and the regulation of circulating self-antigens in autoimmune diseases, such as IBD. Therefore, one potential mechanism is that the depletion of B cells induced regulatory T cell dysfunction and the activation of cytotoxic T cells, resulting in mucosal damage. The differential magnitude of the suppression of regulatory T cells and the activation of Th1 and Th17 induced by B cell depletion after RTX may lead to differences in both the degree of inflammation and affected region in the intestinal mucosa. Determining this mechanism may clarify the pathogenesis of IBD.
Why ileocolitis did not occur when RTX was used in the first line but did occur when used in the third line remains unclear. However, the accumulation of damage to the ileocolic mucosa or additive damage of the combination with yttrium-conjugated ibritumomab tiuxetan may be involved.
Treatments for RTX-induced enterocolitis have not yet been established. However, several agents suggested in the IBD guideline, such as 5-ASA, CSs, azathioprine, and biologics were effective in some cases. Indeed, Shahmohammadi et al. reported that the concomitant use of 5-ASA and CSs was effective in 43% (3/7) of patients (6). Biologics can be added because the efficacy of ustekinumab for RTX-induced Chron's disease has been reported (18).
CSs were effective in our case; however, after ileocolitis remission and B cell recovery in the intestinal mucosa, the MALToma recurred, which is consistent with the case of recurrent autoimmune hepatitis reported by Shahmohammadi et al. and NS reported by Ardelean et al. (6,11). Medications other than RTX may be added if they are confirmed to be effective for controlling the original diseases.
Conclusion
We herein report what is to our knowledge the first case of a Japanese man treated with RTX who developed ileocolitis diagnosed by endoscopy and histological findings and was successfully treated with CSs. RTX-induced ileocolitis should be considered as a differential diagnosis for patients experiencing bloody stool or watery diarrhea after RTX treatment. Furthermore, we should accumulate cases to establish diagnostic criteria and the ideal treatment for RTX-induced ileocolitis.
The authors state that they have no Conflict of Interest (COI). | RITUXIMAB | DrugsGivenReaction | CC BY-NC-ND | 33642561 | 19,072,196 | 2021 |
What was the outcome of reaction 'Enterocolitis'? | Rituximab-induced Ileocolitis in a Patient with Gastric MALToma: A Case Report and Literature Review.
Rituximab (RTX) is effective for treating cancer, but reports of RTX-associated enterocolitis are limited. We herein report the case of a 65-year-old man who developed RTX-induced ileocolitis. He was diagnosed with gastric mucosa-associated lymphoid tissue lymphoma (MALToma) and treated with RTX. He complained of bloody diarrhea after RTX. Mucosal inflammation on colonoscopy indicated RTX-induced ileocolitis. He was treated with corticosteroids, and his symptoms improved. We reviewed the RTX-associated gastrointestinal adverse events and classified the features into ulcerative colitis, Crohn's disease, microscopic colitis, and ileocolitis. To our knowledge, this is the first case of a Japanese patient who developed RTX-induced ileocolitis.
Introduction
Rituximab (RTX), the anti-cluster of differentiation (CD)20 chimeric antibody, depletes both CD19-positive and CD20-positive B cells via various mechanisms (1). This B-cell depletion therapy is effective for treating CD20-positive hematological malignancies, including mucosa-associated lymphoid tissue lymphoma (MALToma), non-Hodgkin lymphoma, and chronic lymphocytic leukemia (2); as well as autoimmune disorders, including rheumatoid arthritis, multiple sclerosis, and nephrotic syndrome.
Gastric lymphomas are classified into mainly MALToma and diffuse large B cell lymphoma, accounting for over 95% of cases, with others including follicular lymphoma, Mantle lymphoma, etc. Among MALTomas, gastric MALToma is primarily induced by Helicobactor pylori infection. Therefore, the first-line therapy is H. pylori eradication (3). When first-line therapy fails, chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and/or RTX are considered as second- or third-line therapy in advanced cases. In addition, radiation therapy is also considered for low-grade primary gastric MALToma.
RTX is well-tolerated in most cases. However, relatively rare and late-onset adverse events have been reported, including gastrointestinal tract issues (4,5). Among patients who received RTX and underwent colonoscopy, 4% were reported to develop RTX-associated colitis (4).
A diagnosis of biologics-induced enterocolitis is based on clinical manifestations, the endoscopic appearance, and histological features. The endoscopic features of immunosuppressive agent-induced enterocolitis have been reported to include ulcerative colitis (UC) (6) and Crohn's disease (7). Microscopic colitis (MC) (8) and ileocolitis induced by RTX (9) have also been reported. To date, only 35 cases of RTX-associated enterocolitis have been reported.
To our knowledge, this is the first reported case of a Japanese man who received RTX for gastric MALToma, developed ileocolitis, and was successfully treated with corticosteroids (CSs).
Case Report
A 65-year-old man was referred to the Department of Gastroenterology at our hospital complaining of bloody diarrhea after RTX therapy for gastric MALToma.
Related medical history and presentation of current illness
He had a history of gastric ulcer with H. pylori infection, which was treated with the standard triple eradication regimen (amoxicillin/clarithromycin/lansoprazole).
He was diagnosed with gastric MALToma following a histological examination of the biopsy specimens from the antral gastric ulcer 4 years after H. pylori eradication. He was admitted to the hematology unit at our hospital. Bone marrow aspiration revealed no lymphoma cells. He was diagnosed with stage IV lymphoma under both the Ann Arbor classification and Lugano International classification due to metastasis in the cervical, subclavian, and mesenteric lymph nodes, as evaluated by computed tomography (CT), abdominal ultrasound, magnetic resonance imaging, and positron emission tomography (PET)-CT.
He was treated with four courses of RTX monotherapy with subsequent treatment of yttrium-conjugated ibritumomab tiuxetan (genetic recombination) and exhibited a partial response (PR). However, four months after the PR, follow-up PET-CT indicated the recurrence of lymphoma in the right cervical lymph nodes. He was treated with another four courses of RTX as the second-line therapy, which resulted in a complete response as evaluated by enhanced CT (data not shown). He complained of watery diarrhea occurring 20 times/day and bloody stool 2 days after the commencement of the second-line RTX therapy. No disease-related family history was reported.
Physical examination findings
A physical examination revealed no anemia, superficial lymph node swelling, or abdominal abnormalities.
Laboratory examination findings
The laboratory examination findings are presented in Table. A blood examination revealed leukocytosis (white blood cell count of 10,680/μL), mild anemia (Hb, 12.3 g/dL), hypersensitive C-reactive protein (CRP) (1.2 mg/L), a high erythrocyte sedimentation rate (ESR) (36 mm/h), cytomegalovirus (CMV) negativity, and human immunodeficiency virus (HIV) negativity. Biochemistry demonstrated no abnormality. His serum interleukin (IL)-2 level was 962 U/mL. The fecal occult blood test was positive. In addition, the fecal culture detected no significant microbiome (bacteria: negative).
Table. Laboratory Examination Findings.
Peripheral blood Biochemistry Hormone and tumor markers Viral antibodies
WBC 10,680 U/µL TP 7.3 g/dL TSH 1.16 µIU/mL CMV-Ag negative
neutrophils 67.8 % Alb 4.2 g/dL free T3 2.24 pg/mL HIV negative
lymphocytes 20.0 % AST 13 U/L free T4 1.18 pg/mL
monocytes 12.1 % ALT 10 U/L sIL-2R 962 U/mL
eosinophils 0.0 % LDH 128 U/L
basophils 0.1 % Cr 0.63 mg/dL
RBC 467 U/µL BUN 5.9 mg/dL
Hb 12.3 g/dL Na 138 mEq/L
Plt 25.7 U/µL Cl 98 mEq/L
ESR 36 mm/h K 3.9 mEq/L
CRP 1.2 mg/dL
WBC: white blood cell count, RBC: red blood cell count, Plt: platelets, ESR: erythrocyte sedimentation rate, TP: total protein, Alb: albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, LDH: lactate dehydrogenase, Cr: chromium, BUN: blood urea nitrogen, Na: sodium, Cl: chlorine, K: potassium, CRP: C-reactive protein, TSH: thyroid-stimulating hormone, sIL-2R: soluble form of interleukin 2 receptor, CMV: cytomegalovirus, HIV: human immunodeficiency virus
Imaging and endoscopic examination findings
Contrast enhanced-CT revealed consecutive circumferential hypertrophy in the terminal ileum through the rectum (Fig. 1). Reddish changes with multiple erosions in gastric antrum were observed by esophagogastroduodenoscopy (EGD) in January 201X before RTX monotherapy with subsequent treatment of yttrium-conjugated ibritumomab tiuxetan treatment (Fig. 2A). A pathological examination with biopsy specimens from the gastric antrum revealed MALToma. EGD revealed atrophic gastritis after H. pylori eradication, whereas ileocolonoscopy (ICS) revealed mild reddish mucosa in the terminal ileum (Fig. 2B), which differed from diffuse consecutive backwash ileitis as occasionally observed in severe UC. ICS showed scattered aphtha and diffuse consecutive inflammation throughout the transverse colon with normal mucosa in some regions (Fig. 2C). In addition, ICS revealed severe erosion and diffuse consecutive inflammation throughout the sigmoid colon and rectum (Fig. 2D).
Figure 1. A, B: Contrast-enhanced computed tomography revealed continuous circumferential hypertrophy from the terminal ileum to the rectum.
Figure 2. Esophagogastroduodenoscopy (EGD) and ileocolonoscopy findings. A: Reddish changes with multiple erosions in the gastric antrum in January 201X before R-CHOP treatment. B: Ileocolonoscopy (ICS) revealed mild reddish mucosa in the terminal ileum. C: ICS revealed scattered aphtha and diffuse consecutive inflammation throughout the transverse colon. D: ICS revealed severe erosion and diffuse consecutive inflammation throughout the sigmoid colon and rectum.
Histological examination findings
Hematoxylin and Eosin (H&E) staining of specimens from the colonic mucosa revealed that plasma cells were dominant in this segment (Fig. 3A), which was consistent with descriptions of RTX-induced colitis in the literature (10).
Figure 3. Histopathological and immunohistochemical findings in colonic mucosa specimens (before treatment) (×100). A: Hematoxylin and Eosin staining of the specimens from the colonic mucosa exhibited diffuse and circumferential erosions, epithelial atrophy, goblet cell reduction, and extensive intestinal inflammation. Furthermore, cryptitis and crypt abscess but not granuloma were observed in the colonic mucosa. B: Immunohistochemistry demonstrated increased CD3+ lymphocytes. C: The complete depletion of CD20+ lymphocytes in the colonic mucosa was demonstrated.
H&E staining of the colorectal mucosa demonstrated diffuse and circumferential erosions, epithelial atrophy, goblet cell reduction, and extensive intestinal inflammation. Furthermore, cryptitis and crypt abscess, but not granuloma, were observed in the colonic mucosa. Cytomegalovirus and pathogenic bacteria were not detected in biopsy specimens. In addition, the ileal erosion specimens indicated lymphocyte infiltration, and these lymphocytes had little atypia (data not shown). Although the presence of a thickened subepithelial collagen band and marked increase in intraepithelial lymphocytes (IELs) were not evaluated, microscopic colitis (MC) was denied, as MC shows endoscopically normal mucosa, in contrast to the present findings.
Immunohistochemistry demonstrated increased CD3-positive lymphocytes and complete depletion of CD20-positive lymphocytes in the colonic mucosa (Fig. 3B, C). In addition, specimens from the ileal erosions revealed CD3+T lymphocytes>CD79alpha+B lymphocytes infiltration. Furthermore, κ and λ chains were equivalent, suggesting no residual MALToma cells.
Differential diagnoses
Crohn's disease, Behçet's disease (BD), non-steroidal anti-inflammatory drug (NSAID)-induced ulcers, and infectious colitis, including bacterial, tuberculosis, and viral colitis, were considered as differential diagnoses.
The final diagnosis
Crohn's disease was excluded due to the absence of longitudinal ulcers or a cobblestone appearance. BD was excluded because no typical round ulcers were observed in the terminal ileum, and the BD diagnostic criteria were not met. The patient had no recent history of NSAID intake. The diagnosis of RTX-induced ileocolitis in the presented patient was thus confirmed based on the clinical, radiological, endoscopic, and histological criteria.
Treatment
The patient was treated with CSs (prednisolone) at a dose of 50 mg/day for 2 weeks. Subsequently CSs were tapered by 5 mg/2-3 weeks (Fig. 4).
Figure 4. Clinical findings. The clinical findings indicate that corticosteroid therapy was effective in ameliorating diarrhea and reducing inflammatory markers. PSL: prednisolone
Outcome and follow-up
The reported bloody diarrhea gradually improved despite CS tapering, and the symptoms had completely disappeared by three months' treatment with CSs. The mucosal and submucosal inflammation (Fig. 5) after additive CS treatment for two months had improved by five months after the start of CS therapy (Fig. 6). At the time of writing, gastric MALToma had not recurred. However, the swelling cervical lymph node was biopsied to reveal the CD30-positive, CD15-positive, pax-5-positive, and EBER-positive lymphoma. The patient was diagnosed with Hodgkin's lymphoma. Two cycles of an ABVD regimen and three cycles of Brentuximab vedotin therapy were administered, and complete remission was achieved. No recurrence had been observed at the time of writing this report.
Figure 5. Endoscopy findings. The endoscopic appearance of mucosal inflammation improved after 5-month corticosteroid treatment. A: Ascending colon, B: transverse colon, C: sigmoid colon, and D: rectum.
Figure 6. Histopathological and immunohistochemical findings (after treatment) (×100). A: Hematoxylin and Eosin staining of the colonic specimens after additive corticosteroid treatment demonstrated a significant reduction in the number of infiltrating inflammatory cells. B: Immunohistochemistry for CD3+ cells indicated a reduction in the infiltration of T cells. C: Immunohistochemistry for CD20+ cells demonstrated the recovery of the scattered infiltration of B cells in colonic mucosa.
Discussion
We herein report the case of a Japanese man who presented with RTX-induced ileocolitis. The patient had been treated for gastric MALToma with four courses of RTX monotherapy with subsequent treatment of yttrium-conjugated ibritumomab tiuxetan (genetic recombination) and exhibited a partial response because the swelling of the right cervical lymph nodes remained, which was indicated by follow-up PET-CT. He was treated with an additional four courses of RTX as third-line therapy, which resulted in a complete response. Thereafter he presented with severe watery diarrhea approximately five months (five doses) after the commencement of the first round of RTX with yttrium-conjugated ibritumomab tiuxetan therapy. The median period and median doses of RTX administered between the first RTX exposure and onset of diarrhea has been reported to be 8 months (4.5-29 months) and 6 doses (5-12 doses), respectively (8); therefore, the median time and administered doses in our case were consistent with those reported previously.
Our patient was 65 years old at the diagnosis. Eckmann et al. reported that the median age of patients diagnosed with inflammatory bowel disease (IBD) after RTX was 52.5 years old (8), which is older than the susceptible age of IBD in the general population, suggesting that the pathogenesis of RTX-associated colitis differs from that of IBD.
Colonoscopy demonstrated moderate-to-severe ileitis and pancolitis. His ileitis resembled Crohn's disease in terms of scattered erosions, and the colitis was similar to UC in terms of the diffuse consecutive circumferential inflammation from the cecum to the rectum. However, no longitudinal ulcers, cobblestone appearance, or skip lesions were observed in the intestine. In addition, the colitis in our patient differed from typical UC in that there was sparse visible vasculature throughout the colon and rectum. Furthermore, the surface appearance of the inflammatory colonic mucosa in this patient indicated the aggregation of small granules. However, small white hues representing cryptitis or crypt abscess are typical findings in UC. Therefore, there is a discrepancy in the mucosal appearance between this patient and typical UC patients. Colonoscopy revealed no punched-out ulcers in the terminal ileum or aphthoid lesions in the colon. Taken together, the colonoscopy findings indicated that our patient did not exhibit typical Crohn's disease, UC, or BD features.
A histological examination of the colonic biopsy specimens demonstrated epithelial atrophy and inflammatory cell infiltration composed of lymphocytes and plasma cells in the epithelium and lamina propria in the focal area. Immunohistochemistry revealed that these infiltrated cells were primarily CD3-positive T cells. CD20-positive B cells were depleted both immediately after RTX treatment and five months after treatment. Ardelean et al. reported a case of RTX-induced severe UC with the infiltration of mature CD3 T cells, cytotoxic CD8 T cells, and forkhead box P3 gene+ regulatory T cells, suggesting that their case was an adverse effect of RTX (11). This evaluation might confirm that the inflammation in the terminal ileum and colon in our case was also an adverse effect of RTX. Although the CD68+ histiocytes and CD68+ small granuloma in the lamina propria suggest the diagnosis of Crohn's disease (7), this finding is not specific to Crohn's disease. In addition, no multinucleate giant cell granuloma, which is typically observed in Crohn's disease, was found in our case. CMV was negative in the biopsy specimens.
Eckmann et al. reported nine cases of MC induced by RTX (8). Collagenous colitis and lymphocytic colitis are included in MC. However, collagen bands in the submucosa and an increase in intraepithelial lymphocytes were not observed in our case, suggesting this was not a case of MC.
With regard to the diagnosis, infectious enterocolitis, including bacterial, viral, and tuberculosis, and the recurrence of MALToma were excluded based on the findings of culture and a histopathological examination. Although yttrium-conjugated ibritumomab tiuxetan might induce or affect ileocolitis, no case of yttrium-conjugated ibritumomab tiuxetan-induced ileocolitis has been reported. Given the present findings, we diagnosed the patient with RTX-induced T cell-mediated ileocolitis.
RTX therapy induced complete depletion of both peripheral and intestinal CD19+ and CD20+ B cells (12). Thereafter, the patient may have developed T cell-mediated intestinal inflammation manifesting as ileocolitis. RTX reportedly exacerbates UC, and B cells can modulate T cell proliferation or activation and induce anti-inflammatory effects via B cell-T cell interaction, as demonstrated by the recovery of mucosal regulatory T cells with the adaptive transfer technique in B cells (13). In our case, the complete depletion of B cells might have caused the downregulation of regulatory cytokines, such as IL-4, transforming growth factor-beta secreted from B cells in gut-associated lymphoid tissue and leading to the upregulation of inflammatory cytokines by activated T cells.
A total of 35 cases of UC, Crohn's disease, MC, and ileocolitis induced by RTX have been reported. Thirteen patients had RTX-induced UC (6,8,11,14), 11 had RTX-induced Crohn's disease (7,8,15,16), 9 had RTX-induced MC, and patients had ileocolitis (9), including our case.
The reason why different RTX-induced diseases (i.e., UC, Crohn's disease, MC, and ileocolitis) present in different patients has not been clarified. However, the loss of B cells might have caused cellular immune dysregulation, followed by the activation of cytotoxic T cells. Indeed, the association of RTX and ileocolitis or enterocolitis was suggested in one study demonstrating the development of severe colitis in B-cell-depleted double-knockout mice (17). In addition, one of the immunosuppressive roles of B cells is the control of pathogenic CD4+ T cells via the production of the regulatory cytokine IL-10 (10,17) and the regulation of circulating self-antigens in autoimmune diseases, such as IBD. Therefore, one potential mechanism is that the depletion of B cells induced regulatory T cell dysfunction and the activation of cytotoxic T cells, resulting in mucosal damage. The differential magnitude of the suppression of regulatory T cells and the activation of Th1 and Th17 induced by B cell depletion after RTX may lead to differences in both the degree of inflammation and affected region in the intestinal mucosa. Determining this mechanism may clarify the pathogenesis of IBD.
Why ileocolitis did not occur when RTX was used in the first line but did occur when used in the third line remains unclear. However, the accumulation of damage to the ileocolic mucosa or additive damage of the combination with yttrium-conjugated ibritumomab tiuxetan may be involved.
Treatments for RTX-induced enterocolitis have not yet been established. However, several agents suggested in the IBD guideline, such as 5-ASA, CSs, azathioprine, and biologics were effective in some cases. Indeed, Shahmohammadi et al. reported that the concomitant use of 5-ASA and CSs was effective in 43% (3/7) of patients (6). Biologics can be added because the efficacy of ustekinumab for RTX-induced Chron's disease has been reported (18).
CSs were effective in our case; however, after ileocolitis remission and B cell recovery in the intestinal mucosa, the MALToma recurred, which is consistent with the case of recurrent autoimmune hepatitis reported by Shahmohammadi et al. and NS reported by Ardelean et al. (6,11). Medications other than RTX may be added if they are confirmed to be effective for controlling the original diseases.
Conclusion
We herein report what is to our knowledge the first case of a Japanese man treated with RTX who developed ileocolitis diagnosed by endoscopy and histological findings and was successfully treated with CSs. RTX-induced ileocolitis should be considered as a differential diagnosis for patients experiencing bloody stool or watery diarrhea after RTX treatment. Furthermore, we should accumulate cases to establish diagnostic criteria and the ideal treatment for RTX-induced ileocolitis.
The authors state that they have no Conflict of Interest (COI). | Recovered | ReactionOutcome | CC BY-NC-ND | 33642561 | 19,072,196 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Potentially Inappropriate Prescriptions to Older Patients in Emergency Departments in South Korea: A Retrospective Study.
The purpose of this study was to evaluate the incidence of the administration of potentially inappropriate medications (PIMs) and the potential drug-drug interactions (pDDIs) in older patients in emergency departments (EDs) over a 12-month period and to identify the factors associated with the administration of PIMs.
This retrospective study was conducted using the electronic medical records from two university-affiliated teaching hospitals in South Korea. ED visit cases of patients aged 65 and older from January 1, 2013, to December 31, 2013, were included in the analysis. Among the medications administered in ED, PIMs or pDDIs were identified using a drug utilization review program available in Korea.
During the study period, a total of 13,002 ED visit cases were reported from 10,686 patients. The proportion of ED visit cases with any PIM was 79.2% and the average number of PIMs was 2.7 (range, 1-17). The most commonly administered PIMs that were contraindicated or should have been used with caution were ketorolac (41.3%) and metoclopramide (10.3%), respectively. Multivariate regression analysis indicated that female patients (p = 0.012), patients with more than six drugs in the ED (p < 0.001), and visits longer than 300 minutes (p = 0.026) were significantly associated with PIM administration in the ED. Potential DDIs between the medications administered in EDs were observed in 20.5% of total visit cases, with ketorolac being the most frequently reported drug in contraindicated drug combinations.
This study demonstrated a high incidence of the administration of PIMs and medications with pDDIs in older patients in EDs and revealed the characteristics that are significantly associated with an increased risk of PIM administration. Healthcare providers in EDs should consider the risk of administering PIMs or medications with pDDIs, especially when treating older patients.
Introduction
The emergency department (ED), the place to institute the immediate medical care of patients with acute illness or injury, is at the intersection between inpatient and outpatient care and can have a meaningful impact on patients’ conditions.1–3 However, EDs are of increasing concern as high-risk environments for potentially inappropriate medication (PIM) use and adverse drug events. Certain characteristics of EDs such as patients overcrowding, a lack of skilled workers, and the high turnover of admitted or discharged patients can hinder the provision of optimal emergency care services.4,5
As the aging of society accelerates, the older adults aged 65 and over account for the largest and fastest growing age group of patients visiting EDs. The proportion of visits by older patients to EDs was reported as 24% in Italy, 31% in Spain, and 22% in the United States.6–8 In Korea, the rate of admission to EDs by older patients has risen from 15.2% in 2005 to 23.9% in 2016.9 Because older adults are sensitive to medicines, the administration of PIMs can lead to adverse drug events, which can have serious medical and safety consequences especially for older adults.10 Moreover, the side effects of these drugs can cause problems long after administration, as many drugs have a longer half-life in the older adults than in younger age people due to changes in pharmacokinetic parameters with aging.11 Some previous studies have shown that exposure to PIMs or potential drug–drug interactions (pDDIs) was associated with an increased risk of re-hospitalization and unplanned hospitalization in the older adults.12–14 Therefore, the need for and importance of appropriate medication use for the older adults visiting EDs should be particularly emphasized.
Potentially inappropriate prescriptions have been well studied in both nursing home and community-dwelling older adult settings. However, less is known about it for older patients visiting EDs. Therefore, the purposes of this study were to determine the incidence and characteristics of PIM use and pDDIs and to identify the factors related to PIM administration, with a particular focus on the older patients visiting EDs.
Patients and Methods
Study Population and Data Collection
This retrospective study was conducted from January to December 2013 at two university-affiliated teaching hospitals in South Korea. Of the patients who visited the EDs in 2013, those aged 65 years and older were included in this study. Patient demographic information and visit characteristics to the EDs were collected from each hospital’s electronic medical records (EMRs). These included the patient’s age, sex, diagnosis in the ED (ICD-10 code), the medications administered in the ED (brand name, ingredient, ATC code), their length of ED stay, and condition after discharge from the ED. Information about the medications that were administered in the ED was prepared by checking the actual dosing time on the EMR, not simply the physician’s order list. To protect the privacy of the patients involved, all data were encoded and protected. This study was conducted with the approval of the Institutional Review Board of Kyung Hee University Hospital at Gangdong (IRB No. 2014-08-003) and Gangneung Asan Hospital (IRB No. 2014–046) in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.
Evaluation of PIMs and pDDIs
Potentially inappropriate medications and pDDIs in the older adults were identified using a commercially available drug utilization review (DUR) database program in Korea (DIKPlus, FirstDIS Ltd, Seoul, Korea). This DUR program provides information on drug–drug interactions, contraindications, and precautions for special population groups such as older adults, children, as well as pregnant and breastfeeding women. For PIMs and pDDIs in older adults, the database was developed by reviewing the Beers Criteria of the American Geriatric Society and the list of drugs to be used with caution in older patients which is provided by the Korea Food and Drug Administration. In addition, product package inserts, US Hospital Preparation Service (AHFS) medication information, Merck manual, US Food and Drug Administration MedWatch and Health Canada were reviewed. Based on these databases, this DUR program classified PIMs in older patients into two groups according to their severity: contraindications (severity level II) and precautions (severity level I). Potential DDIs were classified into three groups: contraindications (severity level III), severe interactions requiring treatment modification (severity level II), and moderate interactions requiring careful monitoring (severity level I).
In this study, medications that are inappropriate only at a specific dose, duration of administration, or comorbid conditions were not included because this information could not be identified. Therefore, the PIMs and pDDIs considered in this study were those listed on the references regardless of diagnosis or condition.
Statistical Analysis
All the statistical analysis was performed on an ED visit, rather than patient case basis. Categorical variables were summarized as values and percentages, and continuous variables were presented as medians and ranges. To understand the characteristics of the medications administered in ED, a descriptive analysis was performed. Multivariate logistic regression analysis was used to identify the predictors of PIM administration. For each ED visit case, the independent variables in the regression model included patient characteristics, such as sex and age, and visit characteristics, such as the number of medications administered and the length of stay. The dependent variable was the PIM occurrence. Two-sided P-values less than 0.05 were considered as statistically significant. All analyses were performed using SAS.
Results
Characteristics of the ED Visit Cases
Table 1 shows the overall characteristics of the ED visit cases. During the study period, a total of 13,002 ED visit cases by 10,686 patients were reported. Some patients had visited the ED more than once (range, 1–18). The median age for the ED visit cases was 74 years (range, 65–104 years). Out of the total cases, 6094 (46.9%) were male and 6908 (53.1%) were female. The median number of diagnoses and medications administered in EDs was 1 (range, 1–3) and 5 (range, 1–55), respectively. The five most common diseases diagnosed in EDs were “Cerebral infarction, unspecified” (545, 4.2%), “Dizziness and giddiness” (463, 3.6%), “Gastroenteritis and colitis of unspecified origin” (336, 2.6%), “Pneumonia, unspecified” (318, 2.5%) and “Unspecified abdominal pain” (204, 1.6%) (Supplementary Table S1). The average length of ED stay was 196 minutes (range, 1–2208 minutes). After the ED visit, there were 6698 cases of hospitalizations (51.5%) and 6154 cases of discharge (47.4%).
Table 1 Characteristics of the ED Visit Cases
Characteristics, No. (%) Total Visit Visit with PIMsa Visit without PIMa P-value
No. of visits 13,002 (100.0) 10,291 (79.1) 2711 (20.9) -
Sex
Male 6094 (46.9) 4776 (46.4) 1318 (48.6) 0.040
Female 6908 (53.1) 5515 (53.6) 1393 (51.4)
Age (year)
65–74 6569 (50.5) 5274 (51.2) 1295 (47.8) 0.005
75–84 4891 (37.6) 3816 (37.1) 1075 (39.7)
≥ 85 1542 (11.9) 1201 (11.7) 341 (12.6)
No. of diagnoses in ED
1 12,484 (96.0) 9888 (96.1) 2596 (95.8) 0.440
≥ 2 518 (4.0) 403 (3.9) 115 (4.2)
No. of medications administered in ED
1–5 7827 (60.2) 5222 (50.7) 2605 (96.1) < 0.001
6–7 2324 (17.9) 2256 (21.9) 68 (2.5)
≥ 8 2851 (21.9) 2813 (27.3) 38 (1.4)
Length of ED stay (minutes)
1–196 6533 (50.2) 5065 (49.2) 1468 (54.1) < 0.001
197–299 3235 (24.9) 2528 (24.6) 707 (26.1)
≥ 300 3234 (24.9) 2698 (26.2) 536 (19.8)
Condition after ED visit
Hospitalization 6698 (51.5) 5439 (52.9) 1259 (46.4) < 0.001
Home 6154 (47.4) 4714 (45.8) 1440 (53.1)
Death 121 (0.9) 116 (1.1) 5 (0.2)
Not assessed 29 (0.2) 22 (0.2) 7 (0.3)
Note:
aEach percentage was calculated out of the total number of corresponding visits.
Abbreviations: ED, emergency department; PIM, potentially inappropriate medication.
Analysis of PIM Use
Of the total ED visit cases, 10,291 (79.2%) contained at least one PIM in their ED administered medication. Between the visit cases with PIMs and those without them, there were significant differences in sex, age, number of medications administered, length of ED stay, and post-discharge status (Table 1).
Of the visit cases with at least one PIM, the average number of PIMs administered in ED was 2.7 (range, 1–17). A total of 7355 (71.5%) visits received ≥2 PIMs, and 4584 (44.5%) visits received ≥3 PIMs. There were 303 (2.9%) visit cases with only PIMs of severity II (contraindications) and 8125 (79.0%) visit cases with only PIMs of severity I (precautions). Moreover, 1863 (18.1%) visit cases had PIMs of both severities I and II (Table 2).
Table 2 Incidence of Visit Cases with PIM
Severity Level No. of Visit with PIMs (%) No. of PIMs Administered, Average (Range)
II only 303 (2.9) 1.2 (1–4)
I only 8125 (79.0) 2.5 (1–16)
II and I 1863 (18.1) 4.2 (2–17)
Abbreviation: PIM, potentially inappropriate medication.
In this study, 22 and 219 PIMs corresponding to severity II and I were administered 2615 and 25,343 times, respectively. The five most commonly administered medications are listed in Table 3. The administered PIMs corresponding to severity II in order of the most common were ketorolac (1081, 41.3%), chlorpheniramine (615, 23.5%), midazolam (236, 9.0%), diazepam (197, 7.5%), and triprolidine/pseudoephedrine (114, 4.4%). These five medications accounted for 85.8% of all the severity level II PIMs. Other medications, including methocarbamol, nifedipine (short-acting), amitriptyline, bisacodyl, and piroxicam accounted for a smaller percentage of the total PIMs (Supplementary Table S2). When analyzed in the same way, the administered PIMs corresponding to severity level I in order of the most common were metoclopramide (2606, 10.3%), famotidine (2312, 9.1%), tramadol (1822, 7.2%), acetaminophen (1269, 5.0%) and nitroglycerine (981, 3.9%). These five medications accounted for 35.5% of all the severity level I PIMs. Other medications such as aspirin, heparin, ranitidine, furosemide, fluoroquinolones (ciprofloxacin, levofloxacin), and opioids (pethidine, fentanyl, morphine) followed (Supplementary Table S3).
Table 3 Top 5 Ranked PIMs
Severity Level Medication n (%)a
Severity II: Contraindications Ketorolac 1081 (41.3)
Chlorpheniramine 615 (23.5)
Midazolam 236 (9.0)
Diazepam 197 (7.5)
Triprolidine/pseudoephedrine 114 (4.4)
Severity I: Precautions Metoclopramide 2606 (10.3)
Famotidine 2312 (9.1)
Tramadol 1822 (7.2)
Acetaminophen 1269 (5.0)
Nitroglycerine 981 (3.9)
Note:
aEach percentage was calculated out of the total number of administration at each severity level.
Abbreviation: PIM, potentially inappropriate medication.
The results of the multivariate logistic regression analysis are noted in Table 4. They indicated that female patients were more associated with increased risk of PIM administration than male patients, and this difference was significant [OR 1.13 (1.03–1.23), p = 0.012]. The visits associated with administered medications numbering six to seven and eight or more had higher risks of PIM administration when compared to the control [OR 16.42 (12.85–21.00), p < 0.001; OR 36.23 (26.21–50.09), p < 0.001; respectively] (Figure 1). It was found that the length of ED stay of more than 300 minutes had a significantly higher risk of PIM administration than the control [1.15 (1.02–1.29), p = 0.026]. However, those aged between 75 and 84 were significantly associated with a decreasing odds ratio of PIM administration [OR 0.88 (0.79–0.97), p = 0.008].
Table 4 Crude and Adjusted Odds Ratios for Factors Influencing PIM Administration
Characteristics Crude Model Adjusted Model
OR (95% CI) P-value OR (95% CI) P-value
Sex
Male 1.00 (Reference) 1.00 (Reference)
Female 1.09 (1.004–1.19) 0.041 1.13 (1.03–1.23) 0.012
Age (years)
65–74 1.00 (Reference) 1.00 (Reference)
75–84 0.87 (0.80–0.96) 0.003 0.88 (0.79–0.97) 0.008
≥ 85 0.87 (0.76–0.99) 0.035 0.87 (0.75–1.002) 0.053
p-for trend 0.004 0.007
No. of medications administered in ED
1–5 1.00 (Reference) 1.00 (Reference)
6–7 16.55 (12.94–21.16) < 0.001 16.42 (12.85–21.00) < 0.001
≥ 8 36.9 (26.71–50.99) < 0.001 36.23 (26.21–50.09) < 0.001
p-for trend < 0.001 < 0.001
Length of ED stay (minutes)
1–196 1.00 (Reference) 1.00 (Reference)
197–299 1.04 (0.94–1.15) 0.491 1.01 (0.90–1.12) 0.903
≥ 300 1.46 (1.31–1.63) < 0.001 1.15 (1.02–1.29) 0.026
p-for trend < 0.001 0.029
Abbreviations: ED, emergency department; PIM, potentially inappropriate medication.
Figure 1 Relationship between PIM incidence and the number of medications administered in ED.
Abbreviations: PIM, potentially inappropriate medication; ED, emergency department.
Analysis of pDDIs
During the study period, pDDI between the medications administered in ED was observed in 2668 visit cases (20.5% of the total visit cases). Potential DDIs corresponding to severity III (contraindications), severity II (severe interactions), and severity I (moderate interactions) were reported from 161 visits (1.2%), 607 visits (4.7%), and 1900 visits (14.6%), respectively. The five most commonly administered medication combinations with respect to the three severity levels are listed in Table 5. The medication combinations corresponding to severity III were in the order of the most common ketorolac-aceclofenac (61, 37.9%), ketorolac-celecoxib (32, 19.9%), ketorolac-ibuprofen (20, 12.4%), levofloxacin-amiodarone (12, 7.5%), and esomeprazole-clopidogrel (10, 6.2%). These five combinations accounted for 83.9% of all the severity level III pDDIs (Supplementary Table S4). When analyzed in the same way, the medication combinations corresponding to severity II were in the order of the most common aspirin-heparin (424, 69.9%), levofloxacin-human insulin (31, 5.1%), ciprofloxacin-human insulin (17, 2.8%), amiodarone-diltiazem (13, 2.1%), and amitriptyline-acetaminophen/tramadol (13, 2.1%), and those corresponding to severity I were in the order of the most common aspirin-clopidogrel (510, 26.8%), heparin-clopidogrel (346, 18.2%), atorvastatin-clopidogrel (181, 9.5%), furosemide-candesartan (73, 3.8%), and levofloxacin-budesonide (47, 2.5%) (Supplementary Table S5 and S6).
Table 5 Top 5 Ranked pDDIs
Severity Level Drug-Drug Interaction n (%)a
Severity III: Contraindications Ketorolac-aceclofenac 61 (37.9)
Ketorolac-celecoxib 32 (19.9)
Ketorolac-ibuprofen 20 (12.4)
Levofloxacin-amiodarone 12 (7.5)
Esomeprazole-clopidogrel 10 (6.2)
Severity II: Severe interactions Aspirin-heparin 424 (69.9)
Levofloxacin-human insulin 31 (5.1)
Ciprofloxacin-human insulin 17 (2.8)
Amiodarone-diltiazem 13 (2.1)
Amitriptyline-acetaminophen/tramadol 13 (2.1)
Severity I: Moderate interactions Aspirin-clopidogrel, 510 (26.8)
Heparin-clopidogrel, 346 (18.2)
Atorvastatin-clopidogrel 181 (9.5)
Furosemide-candesartan 73 (3.8)
Levofloxacin-budesonide 47 (2.5)
Note:
aEach percentage was calculated out of the total number of pDDIs at each severity level.
Abbreviation: pDDIs, potential drug–drug interactions.
Discussion
To the best of our knowledge, this is the first DUR study to focus on the appropriateness of the drugs administered in EDs to older Korean patients. There have been a few studies that have evaluated PIMs in older patients in Korea, but all of them were conducted in outpatient settings or long-term care facilities.15–19 This study observed that, of the total ED visit cases by older patients, 79.2% and 20.5% involved at least one PIM and pDDI in the medications administered in ED, respectively. The independent variables of sex, the number of medications administered in ED, and the length of ED stay were significantly associated with PIM administration.
The overall incidence of PIM administration detected in this study (79.2%) was higher than previous large-scale studies conducted in Western and Asian countries using ED data (15% to 53%).10,20–23 Although Harrison et al reported that 76% of study patients received at least one prescription with PIM according to Beers criteria, the total sample size of their study was small (n = 400).24 The high incidence of the administration of PIMs in this study could be principally explained by the DUR program used in this study, which contains more country-specific medications than the Beers Criteria primarily used in the previous studies. The Beers Criteria has been used to warn of PIM in older patients for a long time, but it is difficult to apply equally to all countries since the available medications and prescription preferences vary by country. In support of this view, Chang et al confirmed that large differences of PIM incidence among older patients in EDs in their study using the Taiwan National Health Insurance Research Database corresponded to differences between country-specific and country non-specific PIM criteria, and they emphasized the importance of establishing country-specific PIM criteria as references for clinical practice in EDs.22
In this study, the frequently administered PIMs corresponding to severity II (contraindication) were usually symptom relief drugs including ketorolac, chlorpheniramine, benzodiazepines such as midazolam and diazepam, and triprolidine/pseudoephedrine. These results are similar to previous studies.10,21–23 Ketorolac is known to cause gastrointestinal toxicity, and chlorpheniramine may cause sedation and urinary retention due to its anticholinergic activity in the older adults. Benzodiazepines have a sedative effect, and there is a risk of hypotension or paradoxical reactions in the older adults. The current study found that each of the five most frequently administered medications of severity II and I accounted for 85.8% and 35.5% of their total PIMs, respectively. Therefore, it would be very beneficial to encourage ED doctors to consider the risk–benefit ratio before prescribing particularly these drugs, to older patients in ED.
The multivariate logistic regression analysis in this study identified female patients, the number of medications administered in ED, and the length of ED stay as factors significantly increasing the risk of PIM administration to older patients visiting EDs, and this is consistent with previous studies.10,21 In this regard, previous studies have explained that females are generally more susceptible to inappropriate prescriptions because they are generally at a higher risk of developing several chronic conditions than males.25,26 In addition, female patients are known to use more sleep-inducing drugs, antidepressants, and analgesics than males, because of their higher prevalence of anxiety disorders, depression, and sleep disorders.27 Interestingly, the incidence of PIM administration was reported to be lower in older patients aged between 75 and 84 years than in the control group (aged between 65 and 74). This result could be explained by ED doctors tending to assess the appropriateness of medications more carefully prior to prescribing to older patients. Further research is needed to clarify the reasons for this observation.
Potential DDIs between the medications administered in ED were also evaluated in this study. The pDDI incidence was 20.5% of total visit cases, and the most frequently reported contraindicated drug combinations were ketorolac and other nonsteroidal anti-inflammatory drugs (NSAIDs). Ketorolac, also the most frequently administered PIM in the current study, can cause serious gastrointestinal problems such as bleeding or peptic ulcers. Its gastrointestinal toxicity is known to be five times stronger than any other NSAID.28 Moreover, ketorolac combinations with other NSAIDs may enhance the risk of gastrointestinal adverse effects.
The prescriptions given in ED are short-term and one-time doses, and the ED situation is generally more critically urgent than that of any other station. Nevertheless, PIMs or pDDIs should be considered carefully since in older patients they can cause severe adverse effects, even in a single dose. Strategies to promote such caution have been applied over the past decade, such as the development of guidelines for the management of medication of the older patients in EDs or software that automatically generates electronic alerts for PIMs or pDDIs in the prescription process.3 However, their effectiveness at ensuring safe medication prescription and administration has had limitations. For example, it was reported that a high percentage (35–96%) of automatically generated electronic alerts were often ignored by doctors because of inadequate alerts for a specific clinical situation or the intended prescription.29 To improve the situation, a more comprehensive review of prescription drugs based on clinical relevance and a better understanding of the unique medical environment of each country is needed. For this, doctor-pharmacist collaboration in ED may be the answer. Recent studies found that pharmacist-assisted medication reconciliation and integration system or academic detailing of physician residents provided by physician–pharmacist pairs contributed to reduce PIM prescription to older patients in ED practices.30,31
The strength of the current study was that it was able to accurately and completely collect patient-specific drug administration records and other details during ED visits using the EMR data collected from two large university-affiliated teaching hospitals. In addition, the PIM criteria used in this study contained more country-specific and substantial data than Beers Criteria which is commonly used criteria in Western countries. This allowed other medications that were not identified as potentially harmful by Beers Criteria (for example, opioid analgesics) to be reviewed in this study. Despite these strengths, this study has some limitations which should be interpreted carefully. First, since this study was conducted with ED data from two hospitals, it is difficult to generalize the study results in different environments. Second, although this study evaluated the incidence of PIM administration or pDDI in EDs, it did not evaluate the actual incidence of associated adverse drug reactions. Finally, this study was conducted in 2013. Nevertheless, we believe that the results of this study may help in promoting safe drug use in older patients in EDs, since PIMs and pDDIs are still recognized as important issues, especially in older patients.
Conclusion
This study demonstrated that older Korean patients were highly exposed to PIMs and medications with pDDIs in the ED. Therefore, healthcare providers in the EDs should carefully consider the risk of administering PMIs or medications with pDDIs, especially when treating female patients, patients who have been prescribed many medications in the ED, and patients who have stayed in the ED for a long time.
Acknowledgments
The authors acknowledge the efforts of Department of Pharmacy of Gang Neung Asan Hospital and Kyung Hee University Hospital at Gangdong for collecting clinical data and providing administrative supports.
Disclosure
The authors declare no potential conflicts of interests. | ACETAMINOPHEN\TRAMADOL HYDROCHLORIDE, AMITRIPTYLINE, CYCLOBENZAPRINE, DULOXETINE, HALOPERIDOL, IMIPRAMINE, NORTRIPTYLINE, QUETIAPINE, TRAMADOL HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33642859 | 19,277,465 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lyme disease'. | Case Report: Borrelia-DNA Revealed the Cause of Arthritis and Dermatitis During Treatment With Rituximab.
Borrelia-specific antibodies in serum did not contribute to the diagnosis of Borrelia arthritis or Borrelia-associated dermatitis in a young woman with ongoing treatment with rituximab due to multiple sclerosis. The diagnosis was confirmed by the detection of Borrelia-DNA in a skin punch biopsy. The patient history did not reveal any tick exposure. She had suffered for several months from fluctuating pain and swelling of the right knee as well as skin involvement with redness and oedema around the ankle of the same leg. Monoarthritis was confirmed by a rheumatologist. Knee puncture was performed but the synovial fluid was only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were found. Borrelia serology in blood revealed borderline levels of immunoglobulin (Ig)M and IgG, respectively. Treatment with doxycycline resulted in resolution of the joint and skin manifestations within a month. This case highlights that Borrelia-specific antibody levels cannot be reliably interpreted in patients who have received B-cell depleting therapy. Under these circumstances, detection of the bacterial genome in different body fluids, such as in the skin, can be a useful complement to the diagnosis of Lyme disease. In this young female, the diagnosis would certainly have been further delayed without the detection of Borrelia-DNA in the skin.
Introduction
An atypical clinical presentation and absence of an adequate immune response to infections are common phenomena in patients with primary immunodeficiency disorders (PID) (1) and multiple sclerosis (MS) (2), as well as in subjects receiving immunosuppressive agents (3). Furthermore, several immune modulating therapies may have similar effects, but this is less well-recognized among physicians lacking deeper knowledge of the impact of the immune system on the pathogenesis and the clinical manifestations of different infectious diseases. As immunomodulating therapies (IMT) are now widely used for a variety of autoimmune and inflammatory diseases, specialists of many different disciplines may need to treat patients using this group of drugs. For instance, patients with MS are often diagnosed and started on treatment at young age and continue for years or decades (4). These circumstances emphasize the importance of physicians being aware of atypical reactions regarding both clinical symptoms and laboratory test results obscuring infections among these patients. This case illustrates that an ongoing infection can easily be overlooked or misinterpreted due to a weak serological response during treatment with a B-cell depleting drug.
Case Presentation
This case illustrates a 20-year-old female diagnosed with MS at the age of 17. She was initially treated with tocilizumab as neuromyelitis optica was suspected due to bilateral optical neuritis and the presence of spinal cord lesions. However, antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein were not detected and the magnetic resonance imaging (MRI) of the brain and spinal cord as well as cerebrospinal fluid (CSF) findings were supportive of MS. Apart from persistent bilateral severely reduced visual acuity she had no other signs of neurological dysfunction. She had previously been in good health and had no family history of PID, or other systemic inflammatory diseases.
Eighteen months prior to the episode of arthritis and skin symptoms reported here, she was started on off-label treatment with rituximab (RTX). RTX is the most frequently used immunomodulatory drug for MS in Sweden according to the Swedish MS registry (5). Initially, she received 1,000 mg of RTX followed by 500–1,000 mg every 6th month, resulting in depletion of circulating B-cells (<0.001 ×109/L). During this period, there were no signs of neuroinflammatory activity of MS.
Clinical Episode
A rheumatologist confirmed the diagnosis of monoarthritis. The right knee had typical signs of inflammation with rubor, tumor, and calor accompanied by a discretely reduced range of motion. The general status was good without fever. The lower right leg was diffusely swollen and two circular erythematous areas around the ankle were seen (Figures 1A,B). A dermatologist interpreted the skin symptoms as possible panniculitis with atypical erythema nodosum as a potential alternative diagnosis. There were no other clinical or laboratory findings of sarcoidosis.
Figure 1 Periarticular swelling of the right leg and ankle. The skin is slightly atrophic adjacent to the two erythematous circular areas seen on the lateral side. The blood vessels appear prominently over the apical part of the foot; a common phenomenon in late cutaneous borreliosis (A). The right knee, calf, and ankle are swollen, without a distinct erythema. Fifteen to twenty degrees deficit in knee extension was observed. Note the dark discoloration of the medial and apical parts of the foot, typically seen in patients with late cutaneous borreliosis (B).
Timeline
Treatment with RTX had been ongoing for approximately one and a half year prior to the onset of arthritis and the cutaneous symptoms had been present for at least 6 months prior to the diagnosis. The last dose of RTX was given 1.5 months before the onset of symptoms related to Lyme disease.
Diagnostic Assessments
Aspiration of synovial fluid resulted in a limited volume, only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were detected in the joint fluid. Duplex ultrasonography of the lower leg showed no signs of deep vein thrombosis and there were no laboratory signs of systemic inflammation. Serological analysis performed 5 months after the last dose of RTX showed borderline levels of immunoglobulin (Ig)M and IgG antibodies against recombinant Borrelia antigens (Liason®, Borrelia IgM detecting OspC and VlsE; Borrelia IgG detecting VlsE). The results were interpreted to be of uncertain clinical significance. Laboratory results are detailed in Table 1.
Table 1 Laboratory findings in blood.
Analyte Results Reference interval
Hemoglobin 151 117–153 g/L
Leukocyte count 7.2 3.5–8.8 ×109/L
Lymphocyte count 1.3 1.1–4.8 ×109/L
B-cells <0.001 0.075–0.53 ×109/L
Platelet count 283 160–390 ×109/L
Erythrocyte sedimentation rate (ESR) 2 <21 mm/h
P-C-reactive protein (CRP) <5 <10 mg/L
S-Creatinine kinase 1.5 <3.6 μkat/L
P-Alanine transaminase 0.35 <0.76 μkat/L
P-Creatinine 81 45–90 μmol/L
P-Urate 209 155–350 μmol/L
S-Angiotensin converting enzyme 0.51 <1.1 μkat/L
Anti-cyclic citrullinated peptide antibody (IgG) 1 <7 U/L
Borrelia antibody (IgM) 38.6 <30 AU/mL
Borrelia antibody (IgG) 16.6 <10 AU/mL
AU, arbitrary units; P-, analysis in plasma; S-, analysis in serum; U, units.
Despite the vague antibody results, there were an enduring clinical suspicion of Borrelia infection. Skin biopsies from one of the erythematous areas at the ankle were performed. Standard histopathology showed mild non-specific inflammation. Borrelia-DNA was detected in the biopsy analyzed by polymerase chain reaction (PCR). The method amplifies a 116 base-pair long fragment of the 16S rRNA gene. In addition, a lumbar puncture was done, and CSF was analyzed without presence of intrathecal Borrelia-specific antibodies or elevated levels of the B-cell chemokine CXCL13. Thus, the final diagnosis was Borrelia associated dermatitis and arthritis (Lyme disease).
Therapeutic Intervention
Prior to the diagnosis of Lyme disease, the patient was prescribed topical steroids for the skin manifestations and the joint symptoms were managed with paracetamol. Once the diagnosis of Lyme disease was confirmed, doxycycline 200 mg once daily for 3 weeks was prescribed. The knee and skin symptoms dissipated during the following month.
Follow-Up and Outcome
At the last follow-up 1 year after the antibiotic treatment had been ended, there was still minor swelling of the lower leg but no signs of arthritis or dermatitis. An MRI of the lower leg showed mild oedema in musculus soleus and gastrocnemius. Creatinine kinase in plasma was within normal reference.
Discussion
IMT in general, and particularly B-cell depleting therapies, may be associated with an increased risk of infections (2, 6, 7). Serological screening for IgG against several infectious agents is therefore routinely performed prior to initiation of IMT and vaccination should be considered when immunity is not detected. However, the fact that IMT can have an impact on the clinical picture and serological response to infectious agents is less well recognized among physicians outside the field of immunology and infectious diseases. B-cell depleting therapies are widely used in MS as well as in many other autoimmune diseases, often with a dramatic anti-inflammatory effect and symptom relief (6). In chronic inflammatory diseases like MS, the treatment is often continued for many years and results in undetectable or very low numbers of circulating B-cells. Although RTX, compared to other disease modifying drugs in MS, has been shown to be associated with an increased risk for serious infections it is widely used due its marked effect on the disease activity and disease progression (4). Another side effect is weak and non-protective responses to vaccinations, as long as the circulating B-cells are very low (8, 9).
In the patient described here, Borrelia caused late skin and joint manifestations that did not raise the clinical suspicion of Lyme disease, until the weak serological response was received. Still, the antibody results were interpreted to be of dubious significance. The correct diagnosis was not made until Borrelia-DNA was detected in the skin biopsy. This is consistent with previous and more recent findings of improved diagnostic accuracy using detection of the Borrelia genome in the skin of patients with acrodermatitis chronica atrophicans, the late cutaneous manifestation of borreliosis (10, 11). In addition, our case clearly illustrates that, during treatment with B-cell depleting therapies, infections may give rise to an atypical clinical picture as well as a weak serological response to specific pathogens. Awareness of these circumstances should be highlighted to clinicians serving patients on IMT.
Patient Perspective
The patient had suffered from knee pain and painful skin erythema for several months before the correct diagnosis was identified. She had been in contact with the primary health care several times before the correct diagnosis was made. Despite the fact that she was treated with IMT, her symptoms were initially interpreted as “non-specific findings of uncertain origin.”
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patient provided her written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable image or data included in this article.
Author Contributions
JS, CS, and CD had full access to all of the data and takes responsibility for the integrity, accuracy and interpretation of the data. All authors contributed to the article and approved the submitted version. All authors were involved in drafting the manuscript or revising it critically for important intellectual content and all authors approved the final version to be published.
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. | ACETAMINOPHEN, RITUXIMAB | DrugsGivenReaction | CC BY | 33643217 | 19,006,938 | 2021 |
What was the outcome of reaction 'Lyme disease'? | Case Report: Borrelia-DNA Revealed the Cause of Arthritis and Dermatitis During Treatment With Rituximab.
Borrelia-specific antibodies in serum did not contribute to the diagnosis of Borrelia arthritis or Borrelia-associated dermatitis in a young woman with ongoing treatment with rituximab due to multiple sclerosis. The diagnosis was confirmed by the detection of Borrelia-DNA in a skin punch biopsy. The patient history did not reveal any tick exposure. She had suffered for several months from fluctuating pain and swelling of the right knee as well as skin involvement with redness and oedema around the ankle of the same leg. Monoarthritis was confirmed by a rheumatologist. Knee puncture was performed but the synovial fluid was only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were found. Borrelia serology in blood revealed borderline levels of immunoglobulin (Ig)M and IgG, respectively. Treatment with doxycycline resulted in resolution of the joint and skin manifestations within a month. This case highlights that Borrelia-specific antibody levels cannot be reliably interpreted in patients who have received B-cell depleting therapy. Under these circumstances, detection of the bacterial genome in different body fluids, such as in the skin, can be a useful complement to the diagnosis of Lyme disease. In this young female, the diagnosis would certainly have been further delayed without the detection of Borrelia-DNA in the skin.
Introduction
An atypical clinical presentation and absence of an adequate immune response to infections are common phenomena in patients with primary immunodeficiency disorders (PID) (1) and multiple sclerosis (MS) (2), as well as in subjects receiving immunosuppressive agents (3). Furthermore, several immune modulating therapies may have similar effects, but this is less well-recognized among physicians lacking deeper knowledge of the impact of the immune system on the pathogenesis and the clinical manifestations of different infectious diseases. As immunomodulating therapies (IMT) are now widely used for a variety of autoimmune and inflammatory diseases, specialists of many different disciplines may need to treat patients using this group of drugs. For instance, patients with MS are often diagnosed and started on treatment at young age and continue for years or decades (4). These circumstances emphasize the importance of physicians being aware of atypical reactions regarding both clinical symptoms and laboratory test results obscuring infections among these patients. This case illustrates that an ongoing infection can easily be overlooked or misinterpreted due to a weak serological response during treatment with a B-cell depleting drug.
Case Presentation
This case illustrates a 20-year-old female diagnosed with MS at the age of 17. She was initially treated with tocilizumab as neuromyelitis optica was suspected due to bilateral optical neuritis and the presence of spinal cord lesions. However, antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein were not detected and the magnetic resonance imaging (MRI) of the brain and spinal cord as well as cerebrospinal fluid (CSF) findings were supportive of MS. Apart from persistent bilateral severely reduced visual acuity she had no other signs of neurological dysfunction. She had previously been in good health and had no family history of PID, or other systemic inflammatory diseases.
Eighteen months prior to the episode of arthritis and skin symptoms reported here, she was started on off-label treatment with rituximab (RTX). RTX is the most frequently used immunomodulatory drug for MS in Sweden according to the Swedish MS registry (5). Initially, she received 1,000 mg of RTX followed by 500–1,000 mg every 6th month, resulting in depletion of circulating B-cells (<0.001 ×109/L). During this period, there were no signs of neuroinflammatory activity of MS.
Clinical Episode
A rheumatologist confirmed the diagnosis of monoarthritis. The right knee had typical signs of inflammation with rubor, tumor, and calor accompanied by a discretely reduced range of motion. The general status was good without fever. The lower right leg was diffusely swollen and two circular erythematous areas around the ankle were seen (Figures 1A,B). A dermatologist interpreted the skin symptoms as possible panniculitis with atypical erythema nodosum as a potential alternative diagnosis. There were no other clinical or laboratory findings of sarcoidosis.
Figure 1 Periarticular swelling of the right leg and ankle. The skin is slightly atrophic adjacent to the two erythematous circular areas seen on the lateral side. The blood vessels appear prominently over the apical part of the foot; a common phenomenon in late cutaneous borreliosis (A). The right knee, calf, and ankle are swollen, without a distinct erythema. Fifteen to twenty degrees deficit in knee extension was observed. Note the dark discoloration of the medial and apical parts of the foot, typically seen in patients with late cutaneous borreliosis (B).
Timeline
Treatment with RTX had been ongoing for approximately one and a half year prior to the onset of arthritis and the cutaneous symptoms had been present for at least 6 months prior to the diagnosis. The last dose of RTX was given 1.5 months before the onset of symptoms related to Lyme disease.
Diagnostic Assessments
Aspiration of synovial fluid resulted in a limited volume, only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were detected in the joint fluid. Duplex ultrasonography of the lower leg showed no signs of deep vein thrombosis and there were no laboratory signs of systemic inflammation. Serological analysis performed 5 months after the last dose of RTX showed borderline levels of immunoglobulin (Ig)M and IgG antibodies against recombinant Borrelia antigens (Liason®, Borrelia IgM detecting OspC and VlsE; Borrelia IgG detecting VlsE). The results were interpreted to be of uncertain clinical significance. Laboratory results are detailed in Table 1.
Table 1 Laboratory findings in blood.
Analyte Results Reference interval
Hemoglobin 151 117–153 g/L
Leukocyte count 7.2 3.5–8.8 ×109/L
Lymphocyte count 1.3 1.1–4.8 ×109/L
B-cells <0.001 0.075–0.53 ×109/L
Platelet count 283 160–390 ×109/L
Erythrocyte sedimentation rate (ESR) 2 <21 mm/h
P-C-reactive protein (CRP) <5 <10 mg/L
S-Creatinine kinase 1.5 <3.6 μkat/L
P-Alanine transaminase 0.35 <0.76 μkat/L
P-Creatinine 81 45–90 μmol/L
P-Urate 209 155–350 μmol/L
S-Angiotensin converting enzyme 0.51 <1.1 μkat/L
Anti-cyclic citrullinated peptide antibody (IgG) 1 <7 U/L
Borrelia antibody (IgM) 38.6 <30 AU/mL
Borrelia antibody (IgG) 16.6 <10 AU/mL
AU, arbitrary units; P-, analysis in plasma; S-, analysis in serum; U, units.
Despite the vague antibody results, there were an enduring clinical suspicion of Borrelia infection. Skin biopsies from one of the erythematous areas at the ankle were performed. Standard histopathology showed mild non-specific inflammation. Borrelia-DNA was detected in the biopsy analyzed by polymerase chain reaction (PCR). The method amplifies a 116 base-pair long fragment of the 16S rRNA gene. In addition, a lumbar puncture was done, and CSF was analyzed without presence of intrathecal Borrelia-specific antibodies or elevated levels of the B-cell chemokine CXCL13. Thus, the final diagnosis was Borrelia associated dermatitis and arthritis (Lyme disease).
Therapeutic Intervention
Prior to the diagnosis of Lyme disease, the patient was prescribed topical steroids for the skin manifestations and the joint symptoms were managed with paracetamol. Once the diagnosis of Lyme disease was confirmed, doxycycline 200 mg once daily for 3 weeks was prescribed. The knee and skin symptoms dissipated during the following month.
Follow-Up and Outcome
At the last follow-up 1 year after the antibiotic treatment had been ended, there was still minor swelling of the lower leg but no signs of arthritis or dermatitis. An MRI of the lower leg showed mild oedema in musculus soleus and gastrocnemius. Creatinine kinase in plasma was within normal reference.
Discussion
IMT in general, and particularly B-cell depleting therapies, may be associated with an increased risk of infections (2, 6, 7). Serological screening for IgG against several infectious agents is therefore routinely performed prior to initiation of IMT and vaccination should be considered when immunity is not detected. However, the fact that IMT can have an impact on the clinical picture and serological response to infectious agents is less well recognized among physicians outside the field of immunology and infectious diseases. B-cell depleting therapies are widely used in MS as well as in many other autoimmune diseases, often with a dramatic anti-inflammatory effect and symptom relief (6). In chronic inflammatory diseases like MS, the treatment is often continued for many years and results in undetectable or very low numbers of circulating B-cells. Although RTX, compared to other disease modifying drugs in MS, has been shown to be associated with an increased risk for serious infections it is widely used due its marked effect on the disease activity and disease progression (4). Another side effect is weak and non-protective responses to vaccinations, as long as the circulating B-cells are very low (8, 9).
In the patient described here, Borrelia caused late skin and joint manifestations that did not raise the clinical suspicion of Lyme disease, until the weak serological response was received. Still, the antibody results were interpreted to be of dubious significance. The correct diagnosis was not made until Borrelia-DNA was detected in the skin biopsy. This is consistent with previous and more recent findings of improved diagnostic accuracy using detection of the Borrelia genome in the skin of patients with acrodermatitis chronica atrophicans, the late cutaneous manifestation of borreliosis (10, 11). In addition, our case clearly illustrates that, during treatment with B-cell depleting therapies, infections may give rise to an atypical clinical picture as well as a weak serological response to specific pathogens. Awareness of these circumstances should be highlighted to clinicians serving patients on IMT.
Patient Perspective
The patient had suffered from knee pain and painful skin erythema for several months before the correct diagnosis was identified. She had been in contact with the primary health care several times before the correct diagnosis was made. Despite the fact that she was treated with IMT, her symptoms were initially interpreted as “non-specific findings of uncertain origin.”
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patient provided her written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable image or data included in this article.
Author Contributions
JS, CS, and CD had full access to all of the data and takes responsibility for the integrity, accuracy and interpretation of the data. All authors contributed to the article and approved the submitted version. All authors were involved in drafting the manuscript or revising it critically for important intellectual content and all authors approved the final version to be published.
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. | Recovering | ReactionOutcome | CC BY | 33643217 | 19,006,938 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Tamoxifen Therapy for Recurrent Mucosal Bleeding in Hereditary Hemorrhagic Telangiectasia.
A 60-year-old Caucasian man had a 55-year history of recurrent severe epistaxis and later presented with multiple gastrointestinal (GI) bleeding from hereditary hemorrhagic telangiectasia (HHT). Bleeding was exacerbated due to coexistent mild hemophilia A. Despite repeated conventional surgical interventions, tranexamic acid and recombinant factor VIII (FVIII) prophylaxis, bleeding episodes worsened in frequency and severity, resulting in the patient becoming transfusion dependent. The introduction of tamoxifen therapy resulted in reduced transfusion requirement.
Introduction
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an autosomal dominant condition. The diagnosis requires at least three out of the four Curacao criteria: 1) Recurrent epistaxis; 2) Telangiectases, typically of the lips, oral cavity, fingers and nose; 3) Telangiectases of the gastrointestinal (GI) tract, arteriovenous malformation (AVM) of lung, brain, liver or spine; 4) Family history of a first degree relative with HHT [1].
Up to 90% of patients with HHT present with recurrent spontaneous epistaxis. Epistaxis and GI bleeding may lead to repeated hospitalizations, severe iron deficiency, anemia and impaired quality of life [2]. Ablative therapy for bleeding telangiectasia provides immediate control, but adjunctive medical therapy is often required. In a recent meta-analysis of medical treatments, Hsu et al [3] concluded that tamoxifen reduced both frequency and severity of epistaxis. We report a patient with HHT complicated by mild hemophilia with severe recurrent bleeding, who became dependent on frequent clotting factors and blood products after failing to respond to conventional therapies.
Case Report
A 60-year-old Caucasian man presented with worsening recurrent GI bleeding causing collapse on a background of HHT and mild hemophilia A (baseline recombinant factor VIII (FVIII) 17%). His hemophilia DNA studies previously demonstrated a single nucleotide change in the A2 domain (c.1804C>G [Arg583>Gly], listed on FVIII mutation databases). He had suffered from recurrent severe epistaxis from age 5. The episodes of epistaxis worsened progressively over the last 15 years, including a major hemorrhage and aspiration during laser therapy requiring intubation and admission to the intensive care unit.
Numerous nasal procedures (septoplasty, buccal flaps, YAG laser and regular coblation) and GI endoscopic interventions (upper endoscopies, double balloon enteroscopy, capsule endoscopy, argon plasma coagulation and hemostatic clip placement) identified and ablated angioectasia of the nasal and upper GI mucosa (Figs. 1, 2). Despite these interventions and the administration of maintenance tranexamic acid and desmopressin (DDAVP) as required, the transfusion requirement peaked at 10 units per month.
Figure 1 Gastroscopy revealed angiodysplasia at the second portion of the duodenum.
Figure 2 Capsule endoscopy revealed angiodysplasia at the proximal part of the small bowel.
Other comorbidities include asthma and longstanding type 2 diabetes with associated painful neuropathy, precluding the use of thalidomide. The multitude of hospital appointments and procedures had a significant negative impact on his career and quality of life, though he managed to remain in full-time employment.
Physical examination revealed pallor and the presence of large telangiectasia of the nasal septum and smaller lesions of the lips, tongue and oral mucosa.
Relevant laboratory investigations demonstrated normocytic anemia, elevated reticulocytes, and raised ferritin (following iron infusion). Historically there had been microcytosis. Other laboratory tests were normal including renal, liver, thyroid function, von Willebrand factor and hemolytic screen.
Due to worsening GI bleeding and epistaxis, tamoxifen 20 mg daily was commenced in August 2019. Hemoglobin and transfusion requirement initially improved, with only occasional, minor self-limiting epistaxis thereafter for the following 6 months. The red blood cell (RBC) transfusion requirement reduced from a peak of 63 units in 6 months, to 16 units in the subsequent 6 months after commencing tamoxifen (Fig. 3). Additionally the requirement for recombinant FVIII reduced from a maximum of 231,000 IU in 6 months to 188,000 IU (19% reduction). Subjective quality of life improved. No side effects of tamoxifen were reported.
Figure 3 Red blood cell (RBC) transfusion trend before and after endoscopy with argon plasma coagulation (APC), YAG laser treatment and initiation of tamoxifen 20 mg daily on August 20, 2019.
After 8 months of tamoxifen therapy this patient developed further severe bleeding from gastric angioectasia, and following successful endoscopic therapy has commenced bevacizumab [4, 5] 5 mg/kg alternate weeks for six doses then monthly. The monthly cost for tamoxifen is $15 and IV bevacizumab is $4,025 ($1,150 for 100 mg/4 mL vital).
Discussion
This case illustrates the management challenges in a patient with severe HHT, transfusion dependent due to significant recurrent bleeding episodes, further compounded by underlying hemophilia A.
HHT is caused by germline mutations in two genes encoding endoglin and anaplastic lymphoma kinase 1 (ALK1). These mutated proteins are expressed in endothelial cells leading to angiodysplasia [6]. The endothelial cells of the telangiectasia have shown increased fibrinolytic activity [7] with the presence of estrogen receptors [8], hence tamoxifen is thought to modify the locally exaggerated fibrinolytic activity [9]. Tamoxifen is a selective estrogen receptor modulator (SERM), typically used as treatment and chemoprevention of breast cancer [10]. Small case series have recently reported some success of tamoxifen therapy for epistaxis in HHT.
A meta-analysis of medical treatment for HHT related epistaxis summarized the available options including oral agents such as estrogen, tranexamic acid and tamoxifen, topical estriol and intranasal bevacizumab. Other potential treatment options include timolol, propranolol, thalidomide, and N-acetylcysteine; however, there have been no randomized controlled studies comparing these therapies. Only tamoxifen showed a statistically significant improvement in frequency and severity of epistaxis at 6-month follow-up when compared with placebo in randomized controlled studies. There were no serious adverse outcomes with the use of tamoxifen [3]. These findings are consistent with this case report.
Tamoxifen is a novel, cheap and widely available therapy, at a cost of NZ$15 per month, and appeared to be effective for reducing bleeding in this case.
Conclusion
This case demonstrates a promising early response to tamoxifen therapy in reducing the frequency and severity of bleeding in HHT. This has not only improved the quality of life for this patient but also reduced the burden of hospitalizations and interventions. We believe that this cheap and widely available therapy should be considered earlier in the management of this group of patients.
None to declare.
Financial Disclosure
None to declare.
Conflict of Interest
The authors declare that they have no conflict of interest.
Informed Consent
Informed consent was obtained from the patient for publication of this case report.
Authors Contributions
SY did the literature reviews and prepared the manuscript. JAB was involved in the diagnosis and management of the patient. JB was involved in correction of the manuscript.
Data Availability
The authors declare that all data concerning this case report are provided within the article. | ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT, TRANEXAMIC ACID | DrugsGivenReaction | CC BY-NC | 33643506 | 19,003,653 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | Tamoxifen Therapy for Recurrent Mucosal Bleeding in Hereditary Hemorrhagic Telangiectasia.
A 60-year-old Caucasian man had a 55-year history of recurrent severe epistaxis and later presented with multiple gastrointestinal (GI) bleeding from hereditary hemorrhagic telangiectasia (HHT). Bleeding was exacerbated due to coexistent mild hemophilia A. Despite repeated conventional surgical interventions, tranexamic acid and recombinant factor VIII (FVIII) prophylaxis, bleeding episodes worsened in frequency and severity, resulting in the patient becoming transfusion dependent. The introduction of tamoxifen therapy resulted in reduced transfusion requirement.
Introduction
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an autosomal dominant condition. The diagnosis requires at least three out of the four Curacao criteria: 1) Recurrent epistaxis; 2) Telangiectases, typically of the lips, oral cavity, fingers and nose; 3) Telangiectases of the gastrointestinal (GI) tract, arteriovenous malformation (AVM) of lung, brain, liver or spine; 4) Family history of a first degree relative with HHT [1].
Up to 90% of patients with HHT present with recurrent spontaneous epistaxis. Epistaxis and GI bleeding may lead to repeated hospitalizations, severe iron deficiency, anemia and impaired quality of life [2]. Ablative therapy for bleeding telangiectasia provides immediate control, but adjunctive medical therapy is often required. In a recent meta-analysis of medical treatments, Hsu et al [3] concluded that tamoxifen reduced both frequency and severity of epistaxis. We report a patient with HHT complicated by mild hemophilia with severe recurrent bleeding, who became dependent on frequent clotting factors and blood products after failing to respond to conventional therapies.
Case Report
A 60-year-old Caucasian man presented with worsening recurrent GI bleeding causing collapse on a background of HHT and mild hemophilia A (baseline recombinant factor VIII (FVIII) 17%). His hemophilia DNA studies previously demonstrated a single nucleotide change in the A2 domain (c.1804C>G [Arg583>Gly], listed on FVIII mutation databases). He had suffered from recurrent severe epistaxis from age 5. The episodes of epistaxis worsened progressively over the last 15 years, including a major hemorrhage and aspiration during laser therapy requiring intubation and admission to the intensive care unit.
Numerous nasal procedures (septoplasty, buccal flaps, YAG laser and regular coblation) and GI endoscopic interventions (upper endoscopies, double balloon enteroscopy, capsule endoscopy, argon plasma coagulation and hemostatic clip placement) identified and ablated angioectasia of the nasal and upper GI mucosa (Figs. 1, 2). Despite these interventions and the administration of maintenance tranexamic acid and desmopressin (DDAVP) as required, the transfusion requirement peaked at 10 units per month.
Figure 1 Gastroscopy revealed angiodysplasia at the second portion of the duodenum.
Figure 2 Capsule endoscopy revealed angiodysplasia at the proximal part of the small bowel.
Other comorbidities include asthma and longstanding type 2 diabetes with associated painful neuropathy, precluding the use of thalidomide. The multitude of hospital appointments and procedures had a significant negative impact on his career and quality of life, though he managed to remain in full-time employment.
Physical examination revealed pallor and the presence of large telangiectasia of the nasal septum and smaller lesions of the lips, tongue and oral mucosa.
Relevant laboratory investigations demonstrated normocytic anemia, elevated reticulocytes, and raised ferritin (following iron infusion). Historically there had been microcytosis. Other laboratory tests were normal including renal, liver, thyroid function, von Willebrand factor and hemolytic screen.
Due to worsening GI bleeding and epistaxis, tamoxifen 20 mg daily was commenced in August 2019. Hemoglobin and transfusion requirement initially improved, with only occasional, minor self-limiting epistaxis thereafter for the following 6 months. The red blood cell (RBC) transfusion requirement reduced from a peak of 63 units in 6 months, to 16 units in the subsequent 6 months after commencing tamoxifen (Fig. 3). Additionally the requirement for recombinant FVIII reduced from a maximum of 231,000 IU in 6 months to 188,000 IU (19% reduction). Subjective quality of life improved. No side effects of tamoxifen were reported.
Figure 3 Red blood cell (RBC) transfusion trend before and after endoscopy with argon plasma coagulation (APC), YAG laser treatment and initiation of tamoxifen 20 mg daily on August 20, 2019.
After 8 months of tamoxifen therapy this patient developed further severe bleeding from gastric angioectasia, and following successful endoscopic therapy has commenced bevacizumab [4, 5] 5 mg/kg alternate weeks for six doses then monthly. The monthly cost for tamoxifen is $15 and IV bevacizumab is $4,025 ($1,150 for 100 mg/4 mL vital).
Discussion
This case illustrates the management challenges in a patient with severe HHT, transfusion dependent due to significant recurrent bleeding episodes, further compounded by underlying hemophilia A.
HHT is caused by germline mutations in two genes encoding endoglin and anaplastic lymphoma kinase 1 (ALK1). These mutated proteins are expressed in endothelial cells leading to angiodysplasia [6]. The endothelial cells of the telangiectasia have shown increased fibrinolytic activity [7] with the presence of estrogen receptors [8], hence tamoxifen is thought to modify the locally exaggerated fibrinolytic activity [9]. Tamoxifen is a selective estrogen receptor modulator (SERM), typically used as treatment and chemoprevention of breast cancer [10]. Small case series have recently reported some success of tamoxifen therapy for epistaxis in HHT.
A meta-analysis of medical treatment for HHT related epistaxis summarized the available options including oral agents such as estrogen, tranexamic acid and tamoxifen, topical estriol and intranasal bevacizumab. Other potential treatment options include timolol, propranolol, thalidomide, and N-acetylcysteine; however, there have been no randomized controlled studies comparing these therapies. Only tamoxifen showed a statistically significant improvement in frequency and severity of epistaxis at 6-month follow-up when compared with placebo in randomized controlled studies. There were no serious adverse outcomes with the use of tamoxifen [3]. These findings are consistent with this case report.
Tamoxifen is a novel, cheap and widely available therapy, at a cost of NZ$15 per month, and appeared to be effective for reducing bleeding in this case.
Conclusion
This case demonstrates a promising early response to tamoxifen therapy in reducing the frequency and severity of bleeding in HHT. This has not only improved the quality of life for this patient but also reduced the burden of hospitalizations and interventions. We believe that this cheap and widely available therapy should be considered earlier in the management of this group of patients.
None to declare.
Financial Disclosure
None to declare.
Conflict of Interest
The authors declare that they have no conflict of interest.
Informed Consent
Informed consent was obtained from the patient for publication of this case report.
Authors Contributions
SY did the literature reviews and prepared the manuscript. JAB was involved in the diagnosis and management of the patient. JB was involved in correction of the manuscript.
Data Availability
The authors declare that all data concerning this case report are provided within the article. | ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT, TRANEXAMIC ACID | DrugsGivenReaction | CC BY-NC | 33643506 | 19,003,653 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaemia'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
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Grade B (Very good): B
Grade C (Good): C
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Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anal fistula'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chest pain'. | Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure.
BACKGROUND
For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery.
OBJECTIVE
To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure.
METHODS
In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis.
RESULTS
Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05).
CONCLUSIONS
Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.
Core Tip: Our data suggest that treatment of locally advanced rectal cancer (LARC) with high-risk factors for failure using total neoadjuvant therapy (TNT) is more effective than standard therapy, achieving a higher rate of pathological complete response, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic chemotherapy. The outcomes of TNT in patients with the most aggressive form of LARC are completely comparable to TNT in all patients with LARC.
INTRODUCTION
Neoadjuvant chemoradiotherapy (CRT), followed by surgery and adjuvant chemotherapy (ChT) is recommended as the standard of care for patients with locally advanced rectal cancer (LARC). While this approach has improved local control, survival remains poor due to distant metastases, which remain the leading cause of death among these patients. The role of adjuvant ChT in the treatment of LARC remains unclear. Adjuvant ChT is often associated with poor tolerance and compliance, the need for dose reduction, and delays in beginning adjuvant treatment due to postoperative complication[1,2]. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby systemic ChT, which mainly affects micrometastasis, is applied with CRT prior to surgery.
Rectal cancer patients who achieve a pathological complete response (pCR) have better disease-free survival, fewer local recurrences, better distant metastasis-free survival, and better overall survival[3]. This fact has become an important guide in testing different strategies to improve the outcome of patients with LARC. Compared to standard treatment, preoperative systemic ChT shows better compliance with ChT, increased downstaging, more margin-negative resections, and a higher rate of pCR[4-7]. Therefore, in the future, this may represent a non-operative approach to selected patients. The highest risk of systemic and/or local failure is found in patients with the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and positive lateral lymph node[8-13].
The aim of this study was to compare the outcomes following TNT or standard therapy in LARC patients with high-risk factors for failure in the same time period.
MATERIALS AND METHODS
This retrospective study included all adult patients with newly-diagnosed LARC with high-risk factors for failure who were treated with TNT or standard therapy at the Institute of Oncology, Ljubljana (Slovenia), from 2016 to 2019. The inclusion criteria were: Histologically-proven rectal adenocarcinoma with distal margin of 15 cm or less from the anal verge on magnetic resonance imaging; Clinical stage II or III; and The presence of at least one of the high-risk factors for failure (T4, N2, mesorectal fascia+, extramural vascular invasion+, and/or lateral lymph node+). Patients were excluded from the study if they had distant metastases, concomitant malignancy, inflammatory bowel disease, or malabsorption syndrome. The study was approved by the local institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Treatment groups
Standard therapy consists of capecitabine-based CRT, followed by surgery and in patients without pCR adjuvant ChT (Figure 1). As part of the preoperative standard therapy, all patients received external-beam radiotherapy using a three-dimensional conformal radiation therapy technique (3D CRT) to the pelvis (45.0 Gy in 25 fractions and a boost to the tumour at a dose of 50.4 Gy for T3 tumours and 54 Gy for T4 tumours, in three to five fractions) and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) to the pelvis (41.8 Gy and simultaneously integrated boost to the tumour at a dose of 46.2 Gy for T3 tumours or 48.4 Gy to T4 tumours in 22 fractions). Concomitant ChT was performed via administration of capecitabine at a daily dose of 825 mg/m2/12 h per os on irradiation day in 3D CRT or from the first to the last irradiation day in IMRT/VMAT. Surgery was scheduled to take place 6-10 wk after completion of CRT. In cases that did not achieve pCR, adjuvant ChT was started at 4-8 wk after surgery. In cases of microscopic residual disease (R1), adjuvant ChT consisted of eight cycles of capecitabine and oxaliplatin (CAPOX). In cases of poor compliance or heart failure, adjuvant ChT consisted of four cycles of 5-fluorouracil and leucovorin.
Figure 1
Timeline and protocol of both treatment groups. CAPOX: Chemotherapy with capecitabine and oxaliplatin; FOLFOX: Chemotherapy with folinic acid, fluorouracil and oxaliplatin.
TNT consisted of induction ChT with CAPOX or with folinic acid, fluorouracil and oxaliplatin (FOLFOX), capecitabine-based CRT and consolidation ChT with CAPOX/FOLFOX prior to surgery. TNT with the CAPOX regimen was defined as four induction cycles (12 wk) of CAPOX, capecitabine-based CRT and two consolidation cycles (6 wk) of CAPOX before surgery. One cycle of the CAPOX regimen involved capecitabine (1000 mg/m2/12 h per os on days 1-14) and oxaliplatin (oxaliplatin 130 mg/m2 intravenous over 2 h on day 1) every 3 wk. In cases with expectation of poorer compliance, patients received the FOLFOX regimen instead of ChT according to the CAPOX regimen. TNT with the FOLFOX regimen was defined as 12 wk of induction ChT and 8 wk of consolidation ChT. The FOLFOX regimen involved 5-fluorouracil (400 mg/m2 intravenous bolus on day 1, then 1200 mg/m2/d for 2 d), oxaliplatin (85 mg/m2 intravenous over 2 h on day 1), and leucovorin (400 mg/m2 intravenous over 2 h on day 1) every 2 wk, twice. CRT in TNT was the same as in standard therapy. Surgery was scheduled to take place 8-10 wk after completion of CRT or 1-2 wk after completion of consolidation ChT.
The study was based upon a cohort of 161 LARC patients who had high-risk factors for failure and who underwent treatment between the years of 2016 and 2019. A total of 72 patients received standard therapy (standard group) and 89 patients received TNT (TNT group). The baseline characteristics for all evaluable patients are listed in Table 1. All patients treated with TNT were pre-treatment staged with computed tomography (CT) of the chest, abdomen and pelvis. Patients treated with standard therapy were pre-treatment staged with CT of the chest, abdomen and pelvis or positron emission tomography-CT (86%); only a minority of patients (14%) had a chest x-ray or abdominal ultrasound in combination with/without CT.
Table 1 Patient characteristics
Characteristic
Standard therapy, n = 72, (%)
TNT, n = 89, (%)
P
value
Age in year < 65 29 (40) 66 (74) < 0.001
≥ 65 43 (60) 23 (26)
Range 40-84 33-79
mean [SD] 65.4 [10.5] 57.5 [10.1] < 0.001
Sex M 45 (63) 54 (61) 0.813
F 27 (38) 35 (39)
PS WHO 0 48 (67) 67 (75) 0.229
1 24 (33) 22 (25)
High-risk factors for failure cT4 15 (21) 33 (37) 0.025
cN2 49 (68) 62 (70) 0.827
MRF+ 39 (54) 66 (74) 0.008
EMVI+ 27 (38) 65 (73) < 0.001
Lateral node 15 (21) 8 (9) 0.033
cTN T2N2 1 (1) 1 (1) 0.1381
T3N0 1 (1) 0 (0)
T3N1 21 (29) 20 (22)
T3N2 34 (47) 35 (39)
T4N1 1 (1) 7 (8)
T4N2 14 (19) 26 (29)
Distance from anal verge in cm ≤ 5 27 (38) 29 (33) 0.370
5.1-10 37 (51) 43 (48)
≥ 10.1 8 (11) 17 (19)
1 Likelihood-ratio test.
EMVI: Extramural vascular invasion; MRF: Mesorectal fascia; PS: Performance status; TNT: Total neoadjuvant treatment; WHO: World Health Organization.
Endpoints
The primary endpoint was pCR rate, which was defined as ypT0N0. Secondary endpoints were neoadjuvant rectal (NAR) score, proportion of T-and N-downstaging, rates of R0 resection, time to stoma closure, acute toxicity, and compliance during treatment. The NAR score was calculated using the equation [5 pN – 3 × (cT-pT) + 12]2 / 9.61 and further classified as low (< 8), intermediate (8-16), or high (< 16)[14,15]. T- or N-downstaging was defined as a reduction in the clinical stage relative to the pathohistological stage. The time to stoma closure was defined as the time from surgery to temporary stoma closure. Treatment-related toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0[16].
Statistics analyses
All statistical analyses were performed using the SPSS statistical software, version 26.0 (IBM Corp., Armonk, NY, United States). Patient and treatment parameters were compared with the χ2 test or Fisher’s exact test for categorical variables and with Student’s t-test for continuous variables. The normality of data distribution was estimated by graphical analysis. In the case of an expected count less than 5 in cells with categorical variables, a likelihood-ratio test was performed, where indicated. A P value of < 0.05 was considered statistically significant. Frequencies and percentages are given in the tables presented herein, unless otherwise indicated. The statistical methods of this study were reviewed by a biomedical statistician holding a PhD in statistics (Rho sigma, https://www.rosigma.si/en/rhosigma).
RESULTS
Efficiency
Patients treated with TNT had a statistically significantly higher proportion of pCR compared to those who received the standard treatment (23% vs 7%; P = 0.007). The odds of achieving pCR were determined to be 3.9-fold higher in the TNT group than in the standard group (odds ratio of 3.92 with a 95% confidence interval of 1.38 to 11.14). The two treatment groups differed significantly in age and in proportion of high-risk factors for failure, but these characteristics alone did not have a significant effect on the rate of pCR. Furthermore, the influence of different characteristics (cT, full dose of systemic ChT, full-dose radiotherapy, all planned preoperative treatment, time from completion of radiotherapy to surgery, presence of acute toxicity, irradiation technique) on the rate of pCR was tested. Among the previously mentioned characteristics, only the irradiation technique showed a statistically significant effect on the rate of pCR in the TNT group, in contrast to the standard therapy group. In detail, we showed a statistically significantly higher proportion of pCR with IMRT/VMAT than with 3D CRT (32% vs 9%; P = 0.03). Similar to the proportion of pCR achievement, the NAR score showed a more favourable distribution in TNT compared to standard treatment (median: 8.43 vs 14.98; P < 0.001) (Table 2).
Table 2 Treatment characteristics
Characteristic
Standard therapy, n = 70, (%)
TNT, n = 82, (%)
P
value
pCR 5 (7) 19 (23) 0.007
CR 7 (10) 23 (26) 0.009
NAR score mean [SD] 16.8 [12.9] 10.7 [10.8] 0.002
NAR classes < 8 9 (13) 35 (43) < 0.001
8-16 38 (56) 33 (40)
> 16 21 (31) 14 (17)
Surgery R0 65 (93) 78 (95) 0.4451
R1 4 (6) 4 (5)
R2 1 (1) 0 (0)
Weeks to stoma closure mean [SD] 32.8 [18.6] 20.1 [10.9] < 0.001
1 Likelihood-ratio test.
CR: Complete response; NAR: Neoadjuvant rectal; pCR: Pathological complete response; TNT: Total neoadjuvant treatment.
Compliance and toxicity
When comparing compliance and toxicity, we found statistically significant differences between the two treatment groups only during the period of systemic ChT administration (Tables 3 and 4). There were no adverse events experienced by patients with grade 4-5 during systemic ChT nor by those with grade 5 during CRT. The proportion of patients completing all planned cycles of systemic ChT was statistically higher in the TNT group than in the standard group. A statistically significant association was observed between the toxicity and the type of treatment administered during systemic ChT. Specifically, in the TNT group there was a slightly higher proportion of patients who experienced toxicity (82% vs 76%) and a higher proportion of patients who experienced adverse events of grades < 3 (79% vs 62%). In spite of that, there was a lower proportion of patients who experienced adverse events of grades 3-5 (3% vs 14%). The most frequent adverse events during systemic ChT were hand-foot syndrome (40%) in the standard group and paraesthesia (61%) in the TNT group (Table 5). The most frequent adverse events of grade 3 during systemic ChT were hand-foot syndrome (10%) in the standard group and hand-foot syndrome (1%), infection (1%) and thromboembolic event (1%) in the TNT group.
Table 3 Treatment compliance during chemoradiotherapy and systemic chemotherapy, n (%)
Standard therapy during CRT
TNT
P
value
Patients who received CRT 72 (100) 88 (99) 0.2751
Patients who received RT 0 (0) 1 (1)
Full-dose ChT (CAP or 5-FU + LV) 62 (86) 67 (75) 0.087
Modification of concomitant ChT 10 (14) 22 (25)
Modification of RT 1 (1) 0 (0)
During adjuvant ChT During systemic ChT
Without ChT due to pCR 5 (7) 0 (0)
Patients who received ChT 50 (72) 89 (100)
All planned cycle
6c of systemic ChT (CAP or CAPOX) 34 (68) 76 (85) 0.0481
Other alternative schemes 4 (8) 2 (2)
No 12 (24) 11 (12)
Full-dose
6c of systemic ChT (CAP or CAPOX) 25 (50) 56 (63) 0.1581
Other alternative schemes 4 (8) 2 (2)
No 21 (42) 31 (35)
1 Likelihood-ratio test.
5-FU: 5-fluorouracil; c: Cycle; CAP: Capecitabine; CAPOX: Capecitabine and oxaliplatin; ChT: Chemotherapy; CRT: Chemoradiotherapy; LV: Leucovorin; pCR: Pathological complete response; RT: Radiotherapy; TNT: Total neoadjuvant treatment.
Table 4 Acute toxicity in all periods in both treatment groups
Toxicity
Standard therapy, n (%)
TNT, n (%)
P
value
During systemic ChT 0.0371
Without 12 (24) 16 (18)
Grade 1-2 31 (62) 70 (79)
Grade 3 7 (14) 3 (3)
During CRT 0.5531
Without 13 (18) 21 (24)
Grade 1-2 57 (79) 64 (72)
Grade 3-4 2 (3) 4 (4)
Postoperative complications 0.140
Without 43 (61) 62 (76)
Grade 1-2 18 (26) 15 (18)
Grade 3-5 9 (13) 5 (6)
1 Likelihood-ratio test.
ChT: Chemotherapy; CRT: Chemoradiotherapy; TNT: Total neoadjuvant treatment.
Table 5 Acute toxicity during systemic chemotherapy in both treatment groups
Toxicity during systemic ChT
Adjuvant ChT (standard therapy), 50 patients
During induction and consolidation ChT (TNT), 89 patients
Grade 1-2
Grade 3
Grade 4
Grade 1-2
Grade 3
Grade 4
Thrombocytopenia 7 14% 0 0 11 12% 0 0
Anaemia 15 30% 0 0 12 13% 0 0
Neutropenia 3 6% 0 0 8 9% 0 0
Diarrhoea 6 12% 1 2% 0 10 11% 0 0
Nausea 2 4% 1 2% 0 29 33% 0 0
Vomiting 2 4% 1 2% 0 8 9% 0 0
Hand foot syndrome 15 30% 5 10% 0 10 11% 1 1% 0
Paraesthesia 1 2% 0 0 54 61% 0 0
Acute renal failure 1 2% 0 0 0 0 0
Rectal fistula 0 1 2% 0 0 0 0
Stoma site infection 1 2% 1 2% 0 0 0 0
Hepatotoxicity 0 0 0 3 3 0 0
Infection 5 10% 0 0 2 2% 1 1% 0
Chest pain 0 0 0 1 1% 0 0
Thromboembolism 5 10% 0 0 1 1% 1 1% 0
Ileus 1 2% 0 0 1 1% 0 0
Enterocolitis 0 0 0 1 1% 0 0
Without toxicity 12 (24%) 16 (18%)
ChT: Chemotherapy; TNT: Total neoadjuvant treatment.
There were no differences between the groups in compliance and acute toxicities during CRT and surgery. In the standard group, 70 (97%) patients underwent surgery, of which 1 patient died a few days after surgery due to septic shock. Two patients who had a clinical complete response refused surgery. In the TNT group, 82 (92%) patients underwent surgery and 6 (7%) patients refused surgery, including 4 patients with clinical complete response among the latter. However, at the end of the first cycle of consolidation ChT, 1 patient developed perineal infection and underwent two non-radical operations at another hospital, dying after the second operation.
DISCUSSION
Through our study, we have confirmed that the treatment of LARC patients with high-risk factors for failure with TNT was statistically significantly better than with standard treatment, in terms of the pCR and NAR score. Despite the fact that the treatment groups differed in age distribution and in the proportions of some high-risk factors for failure, we showed by statistical analysis that these characteristics do not affect achievement of pCR. Moreover, the TNT group had overall greater extent of disease but achieved a higher proportion of pCR. Treatment of LARC patients with high-risk factors for failure by means of TNT is more effective than standard therapy because it achieves a higher rate of pCR, more favourable survival prognosis, higher proportion of T-and N-downstaging, shorter time to temporary stoma closure, better compliance, and lower toxicity grade 3-5 during systemic ChT. To our knowledge, our distribution of the NAR prognostic score in the TNT group is the most favourable of all published studies on the treatment of LARC with near TNT, CRT or neoadjuvant radiotherapy[17-21]. Our patients with the most aggressive form of LARC treated with TNT had a similar rate of pCR as all patients with LARC, which speaks in favour of TNT[22,23].
We showed a statistically significant influence of the irradiation technique on the proportion of pCR in the TNT group. This statistically significant influence was not found in the standard group but a similar trend was observed. One of the reasons why we failed to demonstrate the influence of the irradiation technique on the proportion of pCR in standard treatment could be the small sample size. In the standard group, only 17% of patients were irradiated with IMRT/VMAT, whereas in the TNT group, this was 61%. The higher rate of pCR in the TNT group irradiated with IMRT/VMAT is attributed to the fact that shortening of the overall treatment time, accuracy of irradiation technique and hypofractionation (higher dose per fraction, simultaneous integrated boost) were enabled with IMRT/VMAT application[24]. We believe that in the trials of different TNT approaches, greater emphasis should be placed on the choice of optimal radiotherapy.
To the best of our knowledge, this study is one of the first comparing standard therapy and TNT in LARC patients with high-risk factors for failure, in addition to the RAPIDO trial[25]. We achieved a slightly lower rate of pCR with both treatments than that reported for the RAPIDO trial (7% and 23% vs 14% and 28% respectively)[26]. Conversely, if we focus only on patients who were irradiated with more advanced irradiation techniques, i.e. IMRT/VMAT, we found higher proportions of pCR achievement (17% and 32% vs 14% and 28% respectively) compared to the RAPIDO trial. When comparing our study with the RAPIDO trial, it should be noted that patients in the latter were irradiated with a short-course radiotherapy, whereby the rate of tumour regression is lower and the occurrence of pCR is less likely[27]. On the other hand, it should be noted that in the RAPIDO trial, there was a longer interval between the end of radiotherapy and surgery, which may have affected the higher rate of pCR[3,28,29].
After analysing the results of treatment of this high-risk group of patients in two previous Slovenian studies, we reported 10.5% of pCR in 2011-2013 and 20% in 2014-2015[24,30,31]. Preoperative treatment was more intensive than standard treatment in both studies. In our present study, the standard group had 7% of pCR, which is less than in the two previous Slovenian studies, as expected. This fact suggests that the population of patients with LARC with high-risk factors for failure needs a more intensive preoperative treatment regimen as the only standard therapy, in order to achieve a higher rate of pCR. In addition to different treatment regimens, patients in the two previous Slovenian studies were treated with different irradiation techniques. Generally speaking, our TNT with 3D CRT differed from treatment in patients in 2011-2013 in the more aggressive preoperative systemic ChT, which, however, was not clearly reflected in a higher rate of pCR (9% vs 10.5%). On the other hand, our TNT with IMRT/VMAT differed from treatment in patients in 2014-2015 in additional preoperative systemic ChT, which was clearly reflected in a higher rate of pCR (32% vs 20%). These facts confirm the position of systemic ChT in the preoperative period to achieve more effective downstaging or a high proportion of pCR. In summary, we believe that systemic ChT has a place in the preoperative period but consideration should be given to choosing the more optimal scheme of preoperative systemic ChT. Therefore, the influence of a radiotherapy regimen and of the aggressiveness of systemic ChT on the outcome of treatment must be taken into account when comparing and researching different TNT schemes.
Compliance with all planned cycles of preoperative systemic ChT in the TNT group was statistically significantly better compared to that in the standard group. This is in line with the findings of other randomised studies in LARC patients and LARC patients with high-risk factors for failure[5,25]. Compliance with the systemic ChT of our TNT group is also comparable to compliance in TNT of LARC patients in other studies (86%-100%)[32].
As with compliance, the toxicity between both groups differs most during the period of systemic ChT. Standard treatment showed an 11% higher rate of toxicity grade ≥ 3 compared to TNT (14% vs 3%). Studies of the TNT and near TNT regimen in the treatment of LARC patients with high-risk factors have demonstrated a varied spectrum of the most common preoperative adverse reactions of grades ≥ 3. All rates of the most common grade ≥ 3 adverse reactions were higher (range: 9%–42%) than in our TNT group, where radiodermatitis and hand-foot syndrome were the most common (in 2%)[25,33-39]. It should be noted that our scheme of TNT is, according to the aforementioned studies, the least aggressive, but at the same time having a very comparable rate of pCR. We found a markedly lower rate of toxicity of grades 3-5 during TNT when comparing toxicities reported from the RAPIDO trial (7% vs 48%)[25]. The lower toxicity in our study could be attributed to the fact that our patients received ChT separately in two parts, so we believe that there was a lower likelihood of potentiation of adverse effects. Given the fact that in the RAPIDO trial diarrhoea was the most common adverse effect of grades ≥ 3 in TNT, the difference in toxicity was most likely also due to a various radiotherapy regimen. The high rate of diarrhoea may have been exacerbated by larger fields and irradiation with 3D CRT as short-course radiotherapy in the RAPIDO trial. On the other hand, in our long-course CRT with IMRT/VMAT with a simultaneous integrated boost without dose escalation, we had higher accuracy due to the contribution of various factors, such as the higher accuracy of delineation using planned magnetic resonance imaging and daily checking of the patient's position during the radiotherapy administration[24].
The proportion of postoperative complications in both groups (39% for the standard group and 24% for the TNT group) was comparable to that of other studies researching TNT in LARC. These other studies showed 13%-51% of postoperative complications[32]. Comparing the proportions of postoperative complications with the largest randomised study in the field of treatment of LARC patients with high-risk factors, we found a fairly comparable or even a slightly lower proportion of postoperative complications with standard therapy (39% vs 47%) and, on the other hand, almost a one-half lower proportion of postoperative complications with TNT (24% vs 50%). One reason for this could be a more effective downstaging with our TNT regimen and consequently a lower rate of abdominoperineal excision compared to the RAPIDO trial (17% vs 58%), despite the fact that we had more patients with low-lying tumours (33% vs 22%)[25]. It is known that the rate of postoperative complications is higher after abdominoperineal excision than after sphincter-preserving surgery[40].
Our study has some limitations that need to be considered when favouring TNT over other treatment options for LARC patients with high-risk factors for failure. First, this study used a retrospective design and, therefore, has a lower level of data reliability than does a prospective or randomised study. Second, patients were followed for up to 3 mo after the end of treatment, which is a short period. A longer follow-up is required to determine the impact on local control, disease-free survival and overall survival. TNT is a relatively new approach in the treatment of LARC, and data on 5-year survival parameters are not yet available.
CONCLUSION
The outcome of TNT is better than that of standard treatment in LARC patients with high-risk factors for failure in terms of the pCR rate and the NAR prognostic score. Our study is one of the first to compare standard treatment and TNT in LARC patients with high-risk factors for failure. With TNT administration, we achieved a statistically significantly higher rate of pCR with IMRT/VMAT compared to 3D CRT. The reasons for the higher pCR are the accuracy of the irradiation technique and the possibility of hypofractionation (higher dose per fraction, simultaneous boost to the tumour) and thus shorter irradiation time.
ARTICLE HIGHLIGHTS
Research background
Distant metastases remain the leading cause of death for patients with locally advanced rectal cancer. Systemic chemotherapy that mainly affects micrometastasis is administered with chemoradiotherapy prior to surgery in total neoadjuvant treatment.
Research motivation
Currently, it is unknown which treatment is better for patients with locally advanced rectal cancer and high-risk factors for treatment failure.
Research objectives
To compare the results of total neoadjuvant therapy and standard therapy in patients with locally advanced rectal cancer and high-risk factors for failure in the same time period.
Research methods
We selected patients with locally advanced rectal cancer and high-risk factors for failure who were treated with standard therapy or with total neoadjuvant therapy. High-risk for failure were defined by the presence of at least one of the following factors: T4 status; N2 status; positive mesorectal fascia; extramural vascular invasion; and/or positive lateral lymph node.
Research results
This retrospective study showed that total neoadjuvant therapy yielded a higher proportion of pathological complete response (pCR), lower neoadjuvant rectal score, higher T-and N-downstaging, equivalent R0 resection, shorter time to stoma closure, higher compliance during systemic chemotherapy, lower proportion of acute toxicity grades ≥ 3 during chemotherapy, and equivalent acute toxicity and compliance during chemoradiotherapy and in the postoperative period. With total neoadjuvant therapy, we achieved a statistically significantly higher rate of pCR with intensity-modulated radiotherapy/volumetric modulated arc therapy compared to the three-dimensional conformal radiation therapy technique.
Research conclusions
The outcome of total neoadjuvant therapy is better than that of standard treatment of locally advanced rectal cancer with high-risk factors for failure, in terms of the pCR rate and the neoadjuvant rectal prognostic score.
Research perspectives
Randomized studies are needed to more reliably assess the benefits of total neoadjuvant therapy for locally advanced rectal cancer with high-risk factors for failure.
Institutional review board statement: The study was reviewed and approved by the institutional review boards and the National Medical Ethics Committee of Slovenia (No. 0120-298/2019/5).
Clinical trial registration statement: This study is registered at https://clinicaltrials.gov/ct2/show/NCT0467957. The registration identification number is NCT04679597.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymised clinical data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: The authors declare that they have no financial relationships to disclose.
Manuscript source: Unsolicited manuscript
Peer-review started: September 27, 2020
First decision: December 12, 2020
Article in press: January 7, 2021
Specialty type: Oncology
Country/Territory of origin: Slovenia
Peer-review report’s scientific quality classification
Grade A (Excellent): 0
Grade B (Very good): B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P-Reviewer: Ahmed M, Cheng J S-Editor: Zhang L L-Editor: A P-Editor: Li JH
Data sharing statement
No additional data are available. | CAPECITABINE, FLUOROURACIL, LEUCOVORIN, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33643528 | 19,024,995 | 2021-02-15 |
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