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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Productive cough'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary fibrosis'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | DIVALPROEX SODIUM, PHENYTOIN SODIUM | DrugsGivenReaction | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
What was the administration route of drug 'DIVALPROEX SODIUM'? | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33457203 | 20,032,181 | 2021 |
What was the administration route of drug 'PHENYTOIN SODIUM'? | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33457203 | 20,032,181 | 2021 |
What was the dosage of drug 'DIVALPROEX SODIUM'? | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33457203 | 18,940,086 | 2021 |
What was the dosage of drug 'PHENYTOIN'? | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33457203 | 18,940,086 | 2021 |
What was the outcome of reaction 'Bronchiectasis'? | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | Recovered | ReactionOutcome | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
What was the outcome of reaction 'COVID-19 pneumonia'? | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | Recovered | ReactionOutcome | CC BY-NC-ND | 33457203 | 18,940,086 | 2021 |
What was the outcome of reaction 'Pulmonary fibrosis'? | Evolution of chest CT scan manifestations in a patient recovered from COVID-19 severe pneumonia with acute respiratory distress syndrome.
A male patient with severe pneumonia due to coronavirus disease 2019 (COVID-19) had acute respiratory distress syndrome (ARDS) which developed in the second week since the first symptoms and improved without mechanical ventilation. The patient had epilepsy as a comorbid disease and his routinely consumed antiepileptic drugs were likely to cause alterations of the immune system. Ground-glass opacity (GGO), consolidation, and reticular pattern are typical radiological features of COVID-19 pneumonia. Less common findings were septal thickening, bronchiectasis, pleural thickening, and subpleural involvement. These radiological abnormalities evolve throughout the course of the disease. In this case report, a GGO lesion was seen in thin-section CT scans on the 30th and 45th day since the onset of symptoms. The consolidation subsided with time and on the 65th day, minimal GGO was seen in CT scan without pulmonary fibrosis and bronchiectasis.
1 Introduction
At the end of December 2019, several cases of pneumonia of unknown etiology were seen in several hospitals in Wuhan city, China. Those acute respiratory infections were eventually known to be caused by coronavirus infection (nCoV2) and were officially entitled as coronavirus disease 2019 (COVID-19) by World Health Organization (WHO) [1,2] (see Fig. 1, Fig. 2, Fig. 3).Fig. 1 Chest CT scan on the 30th day of the onset of symptoms (axial and coronal views): Multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions. A pleural band was seen in the lower posterior part of both lungs, and traction bronchiectasis.
Fig. 1
Fig. 2 Chest CT scan on the 45th day of the onset of symptoms (axial and coronal views): GGO was still visible in the posterior and peripheral part of both lungs (improvement compared to the previous CT), with less bronchiectasis and fibrosis.
Fig. 2
Fig. 3 Chest CT scan on the 65th day of the onset of symptoms: (a). Minimal GGO was seen in the inspiration phase, and (b). On the expiration phase, an “enhancement” of GGO lesion was seen due to an increase of intrathoracic pressure without the sign of “air-trapping”.
Fig. 3
Symptoms that are often found in SARS-CoV2 infection are fever and dry cough. Some patients complain of sore throat, runny nose, anosmia, or diarrhea. Based on the data of hospitalized patients, the majority of COVID 19 cases (around 80%) presented without symptoms (asymptomatic) or with mild symptoms, while the rest of the cases had severe symptoms or critical condition [2]. In severe cases, patients complain of shortness of breath and/or had hypoxemia 1 week after the onset of the disease, and promptly develop into acute respiratory distress syndrome (ARDS), septic shock, and death [3]. Ground-glass opacity (GGO), consolidation, reticular pattern are typical radiological features of COVID-19 pneumonia. In survived patients, these radiological features subsided or disappear [4,5].
2 Case presentation
A 35-year-old man came to the hospital with the chief complaint of fever for 5 days. On the sixth day since the onset of fever, the patient complained of coughing when deep inhaling, coughing up phlegm especially after a shower, shortness of breath, odynophagia, and he went to the emergency room. He also complained of nausea, without vomiting, abdominal pain, and diarrhea. The patient had a history of epilepsy since 12 years-old, routinely taking phenytoin and divalproex sodium.
On physical examination, the patient looks dyspnea with respiration rate 20–21 x/min, temperature 37.3 °C, blood pressure 120/80 mmHg, heart rate 108 x/min, chest X-ray revealed peripheral bilateral patchy consolidation, normal laboratory results, CD4 result 322 cells/mm3 (range 410–1.590 cells/mm3). During hospitalization, the patient was given oxygen 2–4 L/min with a nasal cannula. On the 9th day since the onset of symptoms, the patient complained of worsening shortness of breath and his peripheral oxygen saturation was 88% (8 L/min oxygen therapy with face mask), oxygen therapy was increased to 10–12 L/min with non-rebreathing mask and his peripheral oxygen saturation gradually rose to 95%. The result of blood gas analysis (BGA) was: pH 7.43, PaCO2 38.3, PaO2 88.6, HCO3-25, BE 1.0, SaO2 97.3%, (A-a)DO2 153.3, PaO2/FiO2 2.3 with FiO240%. The result of BGA obtained the following day was: pH 7.49, PaCO2 41.7, PaO2 77.0, HCO3-31.2, BE 7.2, SaO2 96.3%, (A-a)DO2 568.1, PaO2/FiO2 0.78 with FiO2 99%. PCR results for SARS-CoV 2 were positive on days 8 and 14 since the onset of the chief complaint. This report has been granted the patient's approval for publication.
A chest computed tomography (CT) scan was performed on supine position with a 64-slice LightSpeed VCT GE Healthcare with a single breath-hold post of inspiration, except for the last CT scan done in two inspirational and expiratory phases. The image was reconstructed with a thickness of 1.2 mm. On the 30th day of the onset of symptoms, a chest CT scan revealed multiple GGO in both lungs, notably in the inferior lobe of the right lung in the posterior and peripheral regions, scantily in the upper left and central right lung, a pleural band in the lower posterior part of both lungs, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma.
On the 45th day of the onset of symptom; GGO was still visible in the peripheral posterior part of both lung (an improvement was seen compared to the previous CT though), the subpleural band was seen in the peripheral posterior part of both lung, there was no visible vascular thickening. Improvement was also seen as the disappearance of bronchiectasis and its surrounding fibrosis. Day 65th chest CT scan illustrated thinner GGO compared to previous CT, without fibrosis or bronchiectasis.
3 Discussion
We presented a case of severe COVID-19 pneumonia complicated with acute respiratory distress syndrome (ARDS) which was diagnosed with WHO criteria [6] who recovered with minimal GGO lesion outcome. ARDS is one of the COVID pneumonia complications with high mortality [7]. Age, high body temperature, comorbidities, neutrophilia, lymphocytopenia, index of impaired organ function, increased index of inflammation, and disorders of coagulopathy are risk factors for ARDS [7]. This patient experienced clinical and oxygenation improvement with medical therapy without mechanical ventilation. He had epilepsy since 12 years-old (rarely having seizure episode) as a comorbid and routinely consumes phenytoin and divalproex sodium. Antiepileptic drugs are known to have an immunosuppressant effect. Carbamazepine or valproic acid affects the concentration of cytokines in the blood. Increased proinflammatory cytokines can lead to immune system disorders [8].
Chest CT scan plays an important role in the diagnosis and follow-up of COVID-19 cases [9]. Early features of thin-section CT in COVID-19 cases are predominantly GGO with reticular pattern and/or interlobar septal thickening. Changes in chest CT scan images in patients with COVID-19 pneumonia begin with a predominance of ground-glass opacity at 0–4 days of the onset of symptom, crazy-paving (reticular) pattern at 5–8 days, consolidation at 9–13 days, and consolidation with a gradual resolution at ≥14 days, but in this phase, a diffuse GGO can be seen as a manifestation of consolidation absorption [10].
Radiological evolution in COVID-19 pneumonia is generally consistent with the clinical course. Shi et al. [5] reported 4 radiological patterns up to week 3 of the disease. 1) Initial progression until the peak which was followed by radiological improvement (46%) and 92% of patients were discharged from the hospital, 2) Radiologically worsened (32%) followed by 11% deaths, 3) Radiologically improved (14%), 63% of patients discharged from the hospital with a median of 19 days hospitalization, 4). No alteration radiologically (9%).
Thin-section chest CT scan with full inspiration since 30th day since the onset of symptoms in this patient showed GGO in both of the lung, pleural band, and traction bronchiectasis secondary to fibrosis of the surrounding lung parenchyma. These findings were consistent with his clinical conditions (shortness of breath during exertion, peripheral oxygen saturation 93–95% on room air, heart rate 110–112 x/min). Improvement of lung sequelae was seen on the 45th day, CT scan results were still dominated by GGO, however less bronchiectasis and fibrosis. The complaint of shortness of breath had subsided, peripheral oxygen saturation 97–98%, heart rate 84–88 x/min, and RT-PCR result had converted to negative. CT scan result of the 65th day revealed minimal GGO, no fibrosis nor air trapping was seen in the thin-section expiratory phase of the CT scan as commonly found in the severe acute respiratory syndrome (SARS) cases [11].
4 Conclusion
We presented a COVID-19 severe pneumonia case with neurological diseases comorbid (epilepsy controlled with antiepileptic drugs) which was complicated by ARDS. High body temperature, neutrophilia, lymphocytopenia, decreased CD4 T cells are risk factors for ARDS. Three follow-ups thin-section chest CT scan since the onset of symptoms revealed an improvement and the outcome was minimal GGO without pulmonary fibrosis or bronchiectasis.
Declaration of competing interest
There was no conflict of interest in this study. No funding was received for this study. Written informed consent was obtained for publication of this case report.
Appendix A Supplementary data
The following is the Supplementary data to this article:Multimedia component 1
Multimedia component 1
Acknowledgement
none.
Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.rmcr.2021.101342. | Recovered | ReactionOutcome | CC BY-NC-ND | 33457203 | 19,948,680 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'. | A Rare Case of Metastatic Colon Cancer in a Patient With Squamous Cell Carcinoma of the Tongue.
Squamous cell carcinoma (SCC) of the colon, both primary and metastatic, are extremely rare malignancies. We present a case of a 60-year-old man with metastatic SCC of the tongue status after radiation and chemotherapy who presented with fatigue and melena. Colonoscopy revealed a 5 cm mass in the transverse colon. Pathology established the diagnosis of poorly differentiated SCC with p16 immunostaining, similar to biopsies from his initially diagnosed lingual cancer. To the best of our knowledge, there are no previously reported cases of primary SCC of the tongue metastasizing to the colon.
INTRODUCTION
Squamous cell cancer (SCC) of the colon is a rare entity and has an incidence of 0.1–0.27 per 1,000 of all colorectal malignancies.1 Colonic metastases from primary SCC of the lung, cervix, and esophagus have previously been reported in the literature.2 These large bowel metastases can occur hematogenously or via transperitoneal seeding from adjacent organs.3 SCC of the head and neck usually metastasizes to the lung, bone, and liver via hematogenous spread.4 Although metastasis of SCC of the head and neck has been reported in the small bowel,5 there have been very few reported cases in the literature recognizing spread to the large intestines. We present a rare case of colonic metastasis in the transverse colon from a lingual SCC. Treatment options are poorly defined, and disease progression despite chemoradiation carries a worse prognosis.6
CASE REPORT
A 60-year-old man was admitted to the hospital with worsening fatigue and melena for 2 weeks. His medical history was significant for stage IV SCC of the tongue (p16+, human papillomavirus [HPV]+), diagnosed 3 years earlier, with metastasis to the lungs and brain. He had undergone surgical resection of the tumor with adjuvant radiation therapy and was receiving pembrolizumab. The patient endorsed intermittent black tarry stools and fatigue for the past few months. Notably, he was admitted 2 months before for persistent dysphagia and odynophagia. At the time, speech-language pathology evaluation found persistent airway invasion during swallowing, for which he underwent upper endoscopy with the placement of percutaneous endoscopic gastrostomy (PEG) tube for supplemental enteral nutrition. Apart from mild candida esophagitis, no other abnormalities were noted on upper endoscopy. Abdominal and pelvic computed tomography performed at that time showed mesenteric lymphadenopathy and jejunal wall thickening that was relatively unchanged from previous imaging. He denied hematemesis, hematochezia, or bleeding through the PEG tube. He endorsed using daily meloxicam for back pain but denied use of any other nonsteroidal anti-inflammatory drug use. He reported a colonoscopy 6 years ago, which was unremarkable. Family history was negative for any gastrointestinal cancer, and he had a previous 35 pack-year smoking history.
On admission, he was hemodynamically stable but cachectic appearing on physical examination. Laboratory testing showed a hemoglobin of 4.3 g/dL. His baseline was 7–8 g/dL. He was appropriately transfused, and the decision was made to proceed with colonoscopy because his upper endoscopic examination 2 months ago was unremarkable. Colonoscopy demonstrated an exophytic ulcerated nonobstructing 5 cm mass suspicious for malignant neoplasm in the transverse colon (Figure 1). Biopsy of the results showed poorly differentiated SCC with ulceration (Figure 2). Stains were positive for p40 and p16, similar to the original pathology report from the resected lingual cancer specimen (Figure 3). Because of the disease progression on pembrolizumab, the patient opted for hospice and comfort care and died 5 weeks later.
Figure 1. A 5 cm exophytic ulcerated mass in the transverse colon.
Figure 2. Poorly differentiated squamous cell carcinoma with ulceration.
Figure 3. Immunostaining positive for P16.
DISCUSSION
Among oropharyngeal squamous cell cancers, cancer from the tongue is the second most common primary site associated with distant spread. In a previous study, the rate of distant metastasis from the lingual SCC was found to be around 4.1%.7 In an analysis of literature from 1937 to 2015 by Irani, involving 67 men and 36 women with distant metastasis from oral SCC, the most common secondary sites of spread were found to be the lungs, heart, and skin.8 Our patient had an unusual site of metastasis from his primary SCC of the tongue. There are 2 cases since 2016 that report metastatic spread to the colon from a head and neck primary SCC, and 1 case of a synchronous metastatic SCC of the colon and cervical lymph nodes with an unknown primary.2,3,9 Our patient had a new colonic mass in the setting of a known primary SCC of the tongue. Our review of literature found this to be the fourth documented case of metastatic SCC of the colon from a head and neck primary and the first such case with the tongue as the primary site of malignancy.
Risk factors for SCC of the head and neck include tobacco use and HPV infection,6 whereas risk factors for distant metastasis include disease extension and achievement of locoregional control.5 In a retrospective study by Hauswald et al looking at 127 patients between 1992 with advanced stage IV SCC of the head and neck, distant metastasis despite chemoradiation had worse long-term outcomes.4 Our patient was a former smoker with endoscopic biopsies of the colonic lesion positive for p16 stain. This is a marker for HPV infection. Furthermore, he continued to have extranodal and regional extension of his disease, despite surgery and chemoradiation, portending a worse prognosis. Although iatrogenic spread of head and neck cancers through PEG tube insertion has been reported in the past,10 our patient did not have risk factors, such as a gastrocolic fistula during insertion or subsequent imaging, which would explain spread to the large bowel from his PEG insertion site.11 More studies are needed to establish, further delineate, and standardize goals of care for such patients.
In patients with known SCC of the head and neck presenting with melena in the setting of a negative esophagogastroduodenoscopy, metastatic disease of the colon should be considered, and a colonoscopy should be included as part the differential workup. Owing to the rarity of the disease, no standardized treatment guidelines currently exist for patients with metastatic SCC of the colon. Prompt surgical evaluation and palliative care consultation are often the mainstays of treatment.
DISCLOSURES
Author contributions: All authors contributed equally to this manuscript. A. Ur Rahman is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report. | PEMBROLIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33457440 | 20,977,090 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Alanine aminotransferase increased'. | A case of relapsed Mycobacterium chelonae pulmonary infection presenting with severe weight loss and treated with a combination of antibiotic therapy and percutaneous feeding.
Mycobacterium chelonae is a type of nontuberculous mycobacteria most commonly associated with skin and soft tissue infections. We present a case of recurrent M. chelonae pulmonary infection presenting with severe weight loss. After recurrence, sputum cultures remained positive for 2 years despite appropriate antibiotics. Cultures only became negative after the addition of intravenous imipenem and jejunostomy feeds. The rarity of M. chelonae pulmonary infection means that optimal treatment regimens have not yet been fully established but a regimen of clarithromycin plus an additional antibiotic has been recommended1. The prognosis of such infections also remains unclear but lower rates of macrolide resistance suggest that the prognosis may be better than the closely related species M. abscessus. Although its benefit has not been proven, nutrition supplementation, including percutaneous enteral feeding, can be considered for refractory NTM infection in underweight patients.
1 Introduction
Nontuberculous mycobacteria (NTM) include over 170 species [2]. Although not all species are pathogenic in humans, some are capable of causing potentially fatal pulmonary and extrapulmonary disease [1]. Further, the prevalence of NTM infections appears to be increasing across much of the world [3]. NTM are frequently classified into slowly-growing and rapidly-growing groups [1]. There are currently 3 main rapidly-growing mycobacterial (RGM) species of clinical importance: M. abcsessus, M. fortuitum and M. chelonae
[4]. M. chelonae most often causes skin and soft tissue infection which can also be a manifestation of disseminated disease [1]. Pulmonary infection has rarely been reported [5].
M. chelonae is commonly found in both natural bodies of water and municipal water supplies and water to is believed to be the usual source of human infection [6]. Risk factors for the development of NTM infection are numerous and include underlying lung disease, immune compromise and a tall slender body habitus especially when associated with pectus excavatum, scoliosis or mitral valve prolapse [7]. In recent years, malnourished status has also been recognized as a risk factor for disease progression in patients with NTM infection [8], [9] although it remains unclear if nutritional supplementation can alter patient outcomes.
We present a case of M. chelonae pulmonary infection successfully treated with a combination of antibiotic therapy and nutritional supplementation.
2 Case presentation
A 61 year-old man initially presented with unexplained weight loss of 9 kg over the preceding 12 months to a weight of 65 kg and a productive cough in June 2005. He had undergone a liver transplant in 2001 for hepatic cirrhosis in the context of hepatitis C infection and prior ethanol abuse. He had undergone a partial gastrectomy in the 1960 s for peptic ulcer disease. He is an ex-smoker with a 20 pack-year history who quit in 1992. During his assessment, he denied any recent dietary changes, night sweats or fevers. Tacrolimus was his only immunosuppressive medication and levels were therapeutic. A CT chest revealed mild bronchiectasis and nodules in the left lower lobe of the lung as well as nodules and patchy groundglass opacities in the right upper lobe (Fig. 1). A CT scan of the abdomen was unremarkable apart from evidence of his prior gastric surgery. A complete blood count, albumin, and bilirubin level were normal. Serum aminotransferases were elevated by approximately 2 times the upper limit of normal on initial assessment but normalized on repeat testing 6 weeks later. Testing for human immunodeficiency virus was negative.Fig. 1 Representitive image from a computed tomography of the chest of a patient with Mycobacterium chelonae pulmonary infection from June 2005. Notable findings in this imageare mild bronchiectasis and nodules in the left lower lobe of the lung.
Sputum cultures performed in September 2005 were positive for M. chelonae. The patient was initiated on rifampin 600 mg daily and clarithromycin 500 mg twice daily. With this therapy, his cough and exercise tolerance improved as did his radiographic abnormalities. Liver enzymes remained normal. By March 2006, he had regained 11 kg and his antibiotics were stopped. A repeat sputum culture was negative for mycobacteria in August 2007.
The patient was then lost to follow up until February 2010 when he presented with fever, cough and weight loss. His weigh had dropped 18.5 kg over at least 2 years and his BMI was 17.9. Repeat human immunodeficiency virus testing was negative. Esophagogastroduodenoscopy showed a small stomach with some retained food but he denied early satiety and regurgitation or symptoms of aspiration. He underwent nutritional counselling with the aim of increasing caloric intake. Two sputum cultures were again positive for M. chelonae.
He was started on moxifloxacin 400 mg daily and clarithromycin 500 mg twice daily in March 2010. Unfortunately, he remained febrile and continued to gradually lose weight. A repeat CT scan of chest revealed progression of bronchiectasis in comparison to 2005 as well as new groundglass opacities diffusely (Fig. 2). Despite therapy, repeat sputum cultures in March 2011 remained positive for M chelonae. Susceptibility testing revealed that the organism was sensitive to amikacin, imipenem and clarithromycin but resistant to ciprofloxacin, linezolid, cefoxitin and trimethoprim-sulfamethoxazole.Fig. 2 Computed tomography of the chest of a patient with recurrence of Mycobacterium chelonae pulmonary infection from June 2010. This image reveals progression of bronchiectasis in comparison to 2005 as well as new groundglass opacities.
He was referred to the mycobacterial disease clinic at our tertiary care centre in March 2012. His weight had fallen to 54.5 kg and sputum cultures were again positive for M. chelonae despite ongoing treatment with clarithromycin and moxifloxacin. His estimated glomerular filtration rate was 35 ml/min/1.73 m2 by diethylenetriaminepentaacetic acid renal scan. His poor renal function was felt to preclude the use of amikacin but imipenem 250 mg twice daily and doxycycline 100 mg twice daily were added to his regimen in April 2012. An elevation in alanine aminotransferase to 5 times the upper limit of normal prompted discontinuation of doxycycline in June 2012. Liver enzymes subsequently returned to baseline. Despite therapy, his weight had continued to decline to 52 kg by August 2012 and a jejunostomy tube was inserted. He received feeds consisting of Resource 2.0 (Nestle Health Science) at 40 cc/hour for 12 h per day in addition to food consumed orally.
With this therapy, his weight increased by 20 kg over 10 months and cough nearly resolved. Three mycobacterial sputum cultures were negative in November 2012 and again in April 2013. By October 2013, he was able to maintain a weight of 69.5 kg with jejunostomy tube feeds held so the tube was removed. Antibiotics were stopped in February 2014. Three mycobacterial sputum cultures were again negative in December 2014. Unfortunately, in May 2016, 1 of 3 sputum cultures was positive for M. chelonae and his weight had dropped to 60 kg. He felt well with no dyspnea and only minimal cough. He has had no progression of radiographic findings or symptoms. As such, he is being followed closely but therapy has not been re-initiated.
3 Discussion
Pulmonary infection with M. chelonae is rare. In a series from a Texas reference laboratory, 154 patients with pulmonary infection from RGM were identified over a 15-year period and only 1 patient was identified as having M. chelonae
[10]. Evaluation of previously published reports regarding M. chelonae is complicated by the evolving taxonomy of the species. Prior to 1992, M. chelonae was not recognized as a separate species from M. abscessus and even some studies published after this date do not differentiate between them [11]. However, differentiation between the two species is important due to differences in treatment and, most likely, prognosis [1], [10].
Given the rarity of the condition, optimal treatment for M. chelonae infection is not yet fully established. Recent guidelines for the treatment of NTM pulmonary disease do not offer specific recommendations for the treatment of this organism [12], [13]. However, previous guidelines suggest a combination of clarithromycin plus one of tobramycin, amikacin linezolid, imipenem, clofazimine, or doxycycline with selection of the additional antibiotic based on in vitro sensitivities [1]. Treatment is recommended to continue until 12 months of negative sputum cultures have been obtained [1].
It should be noted that initial management of the patient was not in keeping with these guidelines. Firstly, antibiotic susceptibility testing does was not performed initially and secondly rifampin is not typically part of recommended treatment [1]. Further, only 20% of M. chelonae isolates are susceptible to ciprofloxacin 20%, which likely translates to a low likelihood of susceptibility to moxifloxacin [1]. The rationale for these treatment decisions is unclear since they occurred prior to referral to our clinic.
In the present case, concerns regarding medication side effects (renal dysfunction and hepatotoxicity) also limited antibiotic options. This is common in the treatment of NTM infections with antibiotic discontinuation or dose reduction reported to occur 18–50% of the time in NTM infection [14].
However, even with optimal treatment, relapse of infection followed by persistent culture positivity despite prolonged antibiotics is common in the treatment of NTM and especially RGM [4]. Among RGM, treatment outcomes are best established for M. abscessus. Patients infected with macrolide-resistant strains of this organism are significantly less likely to achieve sputum culture conversion and relapse is nearly universal among those who do [15]. Macrolide resistance is less common and appears less likely to be induced in vitro by macrolide exposure in M. chelonae compared to M. abscessus
[16]. These findings suggest that M. chelonae pulmonary infection may carry a better prognosis than M. abscessus although this remains somewhat speculative.
In the case we present, weight loss was the predominant feature although cough and dyspnea developed shortly after his initial presentation. The substantial and recurrent weight loss experienced by the patient we present highlights the importance of nutrition in NTM infections. Low body mass index (BMI) is a well established risk factor for NTM infection [17], [18]. Further, nutritional markers including low body weight, body fat and muscle mass have been correlated with an increased risk of progression of radiographic findings in M. avium complex infection [8], [9], [19]. Nonetheless, it is unclear whether weight loss represents a cause or effect of disease progression or indeed whether both are true. Further, to our knowledge the potential benefit of nutritional supplementation has not been evaluated.
In this case, the role played by nutritional supplementation cannot be definitively separated by that played by antibiotic therapy. The patient’s initial regimen of clarithromycin and moxifloxacin was insufficient as evidenced by his ongoing symptoms and positive sputum cultures despite 2 years of continuous therapy. However, the patient’s clinical status deteriorated even after escalation of antibiotic therapy and the initiation of percutaneous enteral feeding was co-incident with both weight gain and subsequent sputum conversion which suggests a probable benefit.
4 Conclusions
M. chelonae is a rare cause of pulmonary infection. Although optimal treatment regimens have not yet been fully established but a regimen of clarithromycin plus an additional antibiotic has been recommended. The prognosis of M. chelonae pulmonary infection also remains unclear but lower rates of macrolide resistance suggest that the prognosis may be better than the closely related species M. abscessus. Although its benefit has not been proven, nutrition supplementation, including percutaneous enteral feeding, can be considered for refractory NTM infection in underweight patients.
5 Ethics Statement
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | CLARITHROMYCIN, DOXYCYCLINE HYCLATE, IMIPENEM, MOXIFLOXACIN, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33458256 | 19,221,460 | 2021-02 |
What is the weight of the patient? | A case of relapsed Mycobacterium chelonae pulmonary infection presenting with severe weight loss and treated with a combination of antibiotic therapy and percutaneous feeding.
Mycobacterium chelonae is a type of nontuberculous mycobacteria most commonly associated with skin and soft tissue infections. We present a case of recurrent M. chelonae pulmonary infection presenting with severe weight loss. After recurrence, sputum cultures remained positive for 2 years despite appropriate antibiotics. Cultures only became negative after the addition of intravenous imipenem and jejunostomy feeds. The rarity of M. chelonae pulmonary infection means that optimal treatment regimens have not yet been fully established but a regimen of clarithromycin plus an additional antibiotic has been recommended1. The prognosis of such infections also remains unclear but lower rates of macrolide resistance suggest that the prognosis may be better than the closely related species M. abscessus. Although its benefit has not been proven, nutrition supplementation, including percutaneous enteral feeding, can be considered for refractory NTM infection in underweight patients.
1 Introduction
Nontuberculous mycobacteria (NTM) include over 170 species [2]. Although not all species are pathogenic in humans, some are capable of causing potentially fatal pulmonary and extrapulmonary disease [1]. Further, the prevalence of NTM infections appears to be increasing across much of the world [3]. NTM are frequently classified into slowly-growing and rapidly-growing groups [1]. There are currently 3 main rapidly-growing mycobacterial (RGM) species of clinical importance: M. abcsessus, M. fortuitum and M. chelonae
[4]. M. chelonae most often causes skin and soft tissue infection which can also be a manifestation of disseminated disease [1]. Pulmonary infection has rarely been reported [5].
M. chelonae is commonly found in both natural bodies of water and municipal water supplies and water to is believed to be the usual source of human infection [6]. Risk factors for the development of NTM infection are numerous and include underlying lung disease, immune compromise and a tall slender body habitus especially when associated with pectus excavatum, scoliosis or mitral valve prolapse [7]. In recent years, malnourished status has also been recognized as a risk factor for disease progression in patients with NTM infection [8], [9] although it remains unclear if nutritional supplementation can alter patient outcomes.
We present a case of M. chelonae pulmonary infection successfully treated with a combination of antibiotic therapy and nutritional supplementation.
2 Case presentation
A 61 year-old man initially presented with unexplained weight loss of 9 kg over the preceding 12 months to a weight of 65 kg and a productive cough in June 2005. He had undergone a liver transplant in 2001 for hepatic cirrhosis in the context of hepatitis C infection and prior ethanol abuse. He had undergone a partial gastrectomy in the 1960 s for peptic ulcer disease. He is an ex-smoker with a 20 pack-year history who quit in 1992. During his assessment, he denied any recent dietary changes, night sweats or fevers. Tacrolimus was his only immunosuppressive medication and levels were therapeutic. A CT chest revealed mild bronchiectasis and nodules in the left lower lobe of the lung as well as nodules and patchy groundglass opacities in the right upper lobe (Fig. 1). A CT scan of the abdomen was unremarkable apart from evidence of his prior gastric surgery. A complete blood count, albumin, and bilirubin level were normal. Serum aminotransferases were elevated by approximately 2 times the upper limit of normal on initial assessment but normalized on repeat testing 6 weeks later. Testing for human immunodeficiency virus was negative.Fig. 1 Representitive image from a computed tomography of the chest of a patient with Mycobacterium chelonae pulmonary infection from June 2005. Notable findings in this imageare mild bronchiectasis and nodules in the left lower lobe of the lung.
Sputum cultures performed in September 2005 were positive for M. chelonae. The patient was initiated on rifampin 600 mg daily and clarithromycin 500 mg twice daily. With this therapy, his cough and exercise tolerance improved as did his radiographic abnormalities. Liver enzymes remained normal. By March 2006, he had regained 11 kg and his antibiotics were stopped. A repeat sputum culture was negative for mycobacteria in August 2007.
The patient was then lost to follow up until February 2010 when he presented with fever, cough and weight loss. His weigh had dropped 18.5 kg over at least 2 years and his BMI was 17.9. Repeat human immunodeficiency virus testing was negative. Esophagogastroduodenoscopy showed a small stomach with some retained food but he denied early satiety and regurgitation or symptoms of aspiration. He underwent nutritional counselling with the aim of increasing caloric intake. Two sputum cultures were again positive for M. chelonae.
He was started on moxifloxacin 400 mg daily and clarithromycin 500 mg twice daily in March 2010. Unfortunately, he remained febrile and continued to gradually lose weight. A repeat CT scan of chest revealed progression of bronchiectasis in comparison to 2005 as well as new groundglass opacities diffusely (Fig. 2). Despite therapy, repeat sputum cultures in March 2011 remained positive for M chelonae. Susceptibility testing revealed that the organism was sensitive to amikacin, imipenem and clarithromycin but resistant to ciprofloxacin, linezolid, cefoxitin and trimethoprim-sulfamethoxazole.Fig. 2 Computed tomography of the chest of a patient with recurrence of Mycobacterium chelonae pulmonary infection from June 2010. This image reveals progression of bronchiectasis in comparison to 2005 as well as new groundglass opacities.
He was referred to the mycobacterial disease clinic at our tertiary care centre in March 2012. His weight had fallen to 54.5 kg and sputum cultures were again positive for M. chelonae despite ongoing treatment with clarithromycin and moxifloxacin. His estimated glomerular filtration rate was 35 ml/min/1.73 m2 by diethylenetriaminepentaacetic acid renal scan. His poor renal function was felt to preclude the use of amikacin but imipenem 250 mg twice daily and doxycycline 100 mg twice daily were added to his regimen in April 2012. An elevation in alanine aminotransferase to 5 times the upper limit of normal prompted discontinuation of doxycycline in June 2012. Liver enzymes subsequently returned to baseline. Despite therapy, his weight had continued to decline to 52 kg by August 2012 and a jejunostomy tube was inserted. He received feeds consisting of Resource 2.0 (Nestle Health Science) at 40 cc/hour for 12 h per day in addition to food consumed orally.
With this therapy, his weight increased by 20 kg over 10 months and cough nearly resolved. Three mycobacterial sputum cultures were negative in November 2012 and again in April 2013. By October 2013, he was able to maintain a weight of 69.5 kg with jejunostomy tube feeds held so the tube was removed. Antibiotics were stopped in February 2014. Three mycobacterial sputum cultures were again negative in December 2014. Unfortunately, in May 2016, 1 of 3 sputum cultures was positive for M. chelonae and his weight had dropped to 60 kg. He felt well with no dyspnea and only minimal cough. He has had no progression of radiographic findings or symptoms. As such, he is being followed closely but therapy has not been re-initiated.
3 Discussion
Pulmonary infection with M. chelonae is rare. In a series from a Texas reference laboratory, 154 patients with pulmonary infection from RGM were identified over a 15-year period and only 1 patient was identified as having M. chelonae
[10]. Evaluation of previously published reports regarding M. chelonae is complicated by the evolving taxonomy of the species. Prior to 1992, M. chelonae was not recognized as a separate species from M. abscessus and even some studies published after this date do not differentiate between them [11]. However, differentiation between the two species is important due to differences in treatment and, most likely, prognosis [1], [10].
Given the rarity of the condition, optimal treatment for M. chelonae infection is not yet fully established. Recent guidelines for the treatment of NTM pulmonary disease do not offer specific recommendations for the treatment of this organism [12], [13]. However, previous guidelines suggest a combination of clarithromycin plus one of tobramycin, amikacin linezolid, imipenem, clofazimine, or doxycycline with selection of the additional antibiotic based on in vitro sensitivities [1]. Treatment is recommended to continue until 12 months of negative sputum cultures have been obtained [1].
It should be noted that initial management of the patient was not in keeping with these guidelines. Firstly, antibiotic susceptibility testing does was not performed initially and secondly rifampin is not typically part of recommended treatment [1]. Further, only 20% of M. chelonae isolates are susceptible to ciprofloxacin 20%, which likely translates to a low likelihood of susceptibility to moxifloxacin [1]. The rationale for these treatment decisions is unclear since they occurred prior to referral to our clinic.
In the present case, concerns regarding medication side effects (renal dysfunction and hepatotoxicity) also limited antibiotic options. This is common in the treatment of NTM infections with antibiotic discontinuation or dose reduction reported to occur 18–50% of the time in NTM infection [14].
However, even with optimal treatment, relapse of infection followed by persistent culture positivity despite prolonged antibiotics is common in the treatment of NTM and especially RGM [4]. Among RGM, treatment outcomes are best established for M. abscessus. Patients infected with macrolide-resistant strains of this organism are significantly less likely to achieve sputum culture conversion and relapse is nearly universal among those who do [15]. Macrolide resistance is less common and appears less likely to be induced in vitro by macrolide exposure in M. chelonae compared to M. abscessus
[16]. These findings suggest that M. chelonae pulmonary infection may carry a better prognosis than M. abscessus although this remains somewhat speculative.
In the case we present, weight loss was the predominant feature although cough and dyspnea developed shortly after his initial presentation. The substantial and recurrent weight loss experienced by the patient we present highlights the importance of nutrition in NTM infections. Low body mass index (BMI) is a well established risk factor for NTM infection [17], [18]. Further, nutritional markers including low body weight, body fat and muscle mass have been correlated with an increased risk of progression of radiographic findings in M. avium complex infection [8], [9], [19]. Nonetheless, it is unclear whether weight loss represents a cause or effect of disease progression or indeed whether both are true. Further, to our knowledge the potential benefit of nutritional supplementation has not been evaluated.
In this case, the role played by nutritional supplementation cannot be definitively separated by that played by antibiotic therapy. The patient’s initial regimen of clarithromycin and moxifloxacin was insufficient as evidenced by his ongoing symptoms and positive sputum cultures despite 2 years of continuous therapy. However, the patient’s clinical status deteriorated even after escalation of antibiotic therapy and the initiation of percutaneous enteral feeding was co-incident with both weight gain and subsequent sputum conversion which suggests a probable benefit.
4 Conclusions
M. chelonae is a rare cause of pulmonary infection. Although optimal treatment regimens have not yet been fully established but a regimen of clarithromycin plus an additional antibiotic has been recommended. The prognosis of M. chelonae pulmonary infection also remains unclear but lower rates of macrolide resistance suggest that the prognosis may be better than the closely related species M. abscessus. Although its benefit has not been proven, nutrition supplementation, including percutaneous enteral feeding, can be considered for refractory NTM infection in underweight patients.
5 Ethics Statement
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | 54.5 kg. | Weight | CC BY-NC-ND | 33458256 | 19,221,460 | 2021-02 |
What was the administration route of drug 'IMIPENEM'? | A case of relapsed Mycobacterium chelonae pulmonary infection presenting with severe weight loss and treated with a combination of antibiotic therapy and percutaneous feeding.
Mycobacterium chelonae is a type of nontuberculous mycobacteria most commonly associated with skin and soft tissue infections. We present a case of recurrent M. chelonae pulmonary infection presenting with severe weight loss. After recurrence, sputum cultures remained positive for 2 years despite appropriate antibiotics. Cultures only became negative after the addition of intravenous imipenem and jejunostomy feeds. The rarity of M. chelonae pulmonary infection means that optimal treatment regimens have not yet been fully established but a regimen of clarithromycin plus an additional antibiotic has been recommended1. The prognosis of such infections also remains unclear but lower rates of macrolide resistance suggest that the prognosis may be better than the closely related species M. abscessus. Although its benefit has not been proven, nutrition supplementation, including percutaneous enteral feeding, can be considered for refractory NTM infection in underweight patients.
1 Introduction
Nontuberculous mycobacteria (NTM) include over 170 species [2]. Although not all species are pathogenic in humans, some are capable of causing potentially fatal pulmonary and extrapulmonary disease [1]. Further, the prevalence of NTM infections appears to be increasing across much of the world [3]. NTM are frequently classified into slowly-growing and rapidly-growing groups [1]. There are currently 3 main rapidly-growing mycobacterial (RGM) species of clinical importance: M. abcsessus, M. fortuitum and M. chelonae
[4]. M. chelonae most often causes skin and soft tissue infection which can also be a manifestation of disseminated disease [1]. Pulmonary infection has rarely been reported [5].
M. chelonae is commonly found in both natural bodies of water and municipal water supplies and water to is believed to be the usual source of human infection [6]. Risk factors for the development of NTM infection are numerous and include underlying lung disease, immune compromise and a tall slender body habitus especially when associated with pectus excavatum, scoliosis or mitral valve prolapse [7]. In recent years, malnourished status has also been recognized as a risk factor for disease progression in patients with NTM infection [8], [9] although it remains unclear if nutritional supplementation can alter patient outcomes.
We present a case of M. chelonae pulmonary infection successfully treated with a combination of antibiotic therapy and nutritional supplementation.
2 Case presentation
A 61 year-old man initially presented with unexplained weight loss of 9 kg over the preceding 12 months to a weight of 65 kg and a productive cough in June 2005. He had undergone a liver transplant in 2001 for hepatic cirrhosis in the context of hepatitis C infection and prior ethanol abuse. He had undergone a partial gastrectomy in the 1960 s for peptic ulcer disease. He is an ex-smoker with a 20 pack-year history who quit in 1992. During his assessment, he denied any recent dietary changes, night sweats or fevers. Tacrolimus was his only immunosuppressive medication and levels were therapeutic. A CT chest revealed mild bronchiectasis and nodules in the left lower lobe of the lung as well as nodules and patchy groundglass opacities in the right upper lobe (Fig. 1). A CT scan of the abdomen was unremarkable apart from evidence of his prior gastric surgery. A complete blood count, albumin, and bilirubin level were normal. Serum aminotransferases were elevated by approximately 2 times the upper limit of normal on initial assessment but normalized on repeat testing 6 weeks later. Testing for human immunodeficiency virus was negative.Fig. 1 Representitive image from a computed tomography of the chest of a patient with Mycobacterium chelonae pulmonary infection from June 2005. Notable findings in this imageare mild bronchiectasis and nodules in the left lower lobe of the lung.
Sputum cultures performed in September 2005 were positive for M. chelonae. The patient was initiated on rifampin 600 mg daily and clarithromycin 500 mg twice daily. With this therapy, his cough and exercise tolerance improved as did his radiographic abnormalities. Liver enzymes remained normal. By March 2006, he had regained 11 kg and his antibiotics were stopped. A repeat sputum culture was negative for mycobacteria in August 2007.
The patient was then lost to follow up until February 2010 when he presented with fever, cough and weight loss. His weigh had dropped 18.5 kg over at least 2 years and his BMI was 17.9. Repeat human immunodeficiency virus testing was negative. Esophagogastroduodenoscopy showed a small stomach with some retained food but he denied early satiety and regurgitation or symptoms of aspiration. He underwent nutritional counselling with the aim of increasing caloric intake. Two sputum cultures were again positive for M. chelonae.
He was started on moxifloxacin 400 mg daily and clarithromycin 500 mg twice daily in March 2010. Unfortunately, he remained febrile and continued to gradually lose weight. A repeat CT scan of chest revealed progression of bronchiectasis in comparison to 2005 as well as new groundglass opacities diffusely (Fig. 2). Despite therapy, repeat sputum cultures in March 2011 remained positive for M chelonae. Susceptibility testing revealed that the organism was sensitive to amikacin, imipenem and clarithromycin but resistant to ciprofloxacin, linezolid, cefoxitin and trimethoprim-sulfamethoxazole.Fig. 2 Computed tomography of the chest of a patient with recurrence of Mycobacterium chelonae pulmonary infection from June 2010. This image reveals progression of bronchiectasis in comparison to 2005 as well as new groundglass opacities.
He was referred to the mycobacterial disease clinic at our tertiary care centre in March 2012. His weight had fallen to 54.5 kg and sputum cultures were again positive for M. chelonae despite ongoing treatment with clarithromycin and moxifloxacin. His estimated glomerular filtration rate was 35 ml/min/1.73 m2 by diethylenetriaminepentaacetic acid renal scan. His poor renal function was felt to preclude the use of amikacin but imipenem 250 mg twice daily and doxycycline 100 mg twice daily were added to his regimen in April 2012. An elevation in alanine aminotransferase to 5 times the upper limit of normal prompted discontinuation of doxycycline in June 2012. Liver enzymes subsequently returned to baseline. Despite therapy, his weight had continued to decline to 52 kg by August 2012 and a jejunostomy tube was inserted. He received feeds consisting of Resource 2.0 (Nestle Health Science) at 40 cc/hour for 12 h per day in addition to food consumed orally.
With this therapy, his weight increased by 20 kg over 10 months and cough nearly resolved. Three mycobacterial sputum cultures were negative in November 2012 and again in April 2013. By October 2013, he was able to maintain a weight of 69.5 kg with jejunostomy tube feeds held so the tube was removed. Antibiotics were stopped in February 2014. Three mycobacterial sputum cultures were again negative in December 2014. Unfortunately, in May 2016, 1 of 3 sputum cultures was positive for M. chelonae and his weight had dropped to 60 kg. He felt well with no dyspnea and only minimal cough. He has had no progression of radiographic findings or symptoms. As such, he is being followed closely but therapy has not been re-initiated.
3 Discussion
Pulmonary infection with M. chelonae is rare. In a series from a Texas reference laboratory, 154 patients with pulmonary infection from RGM were identified over a 15-year period and only 1 patient was identified as having M. chelonae
[10]. Evaluation of previously published reports regarding M. chelonae is complicated by the evolving taxonomy of the species. Prior to 1992, M. chelonae was not recognized as a separate species from M. abscessus and even some studies published after this date do not differentiate between them [11]. However, differentiation between the two species is important due to differences in treatment and, most likely, prognosis [1], [10].
Given the rarity of the condition, optimal treatment for M. chelonae infection is not yet fully established. Recent guidelines for the treatment of NTM pulmonary disease do not offer specific recommendations for the treatment of this organism [12], [13]. However, previous guidelines suggest a combination of clarithromycin plus one of tobramycin, amikacin linezolid, imipenem, clofazimine, or doxycycline with selection of the additional antibiotic based on in vitro sensitivities [1]. Treatment is recommended to continue until 12 months of negative sputum cultures have been obtained [1].
It should be noted that initial management of the patient was not in keeping with these guidelines. Firstly, antibiotic susceptibility testing does was not performed initially and secondly rifampin is not typically part of recommended treatment [1]. Further, only 20% of M. chelonae isolates are susceptible to ciprofloxacin 20%, which likely translates to a low likelihood of susceptibility to moxifloxacin [1]. The rationale for these treatment decisions is unclear since they occurred prior to referral to our clinic.
In the present case, concerns regarding medication side effects (renal dysfunction and hepatotoxicity) also limited antibiotic options. This is common in the treatment of NTM infections with antibiotic discontinuation or dose reduction reported to occur 18–50% of the time in NTM infection [14].
However, even with optimal treatment, relapse of infection followed by persistent culture positivity despite prolonged antibiotics is common in the treatment of NTM and especially RGM [4]. Among RGM, treatment outcomes are best established for M. abscessus. Patients infected with macrolide-resistant strains of this organism are significantly less likely to achieve sputum culture conversion and relapse is nearly universal among those who do [15]. Macrolide resistance is less common and appears less likely to be induced in vitro by macrolide exposure in M. chelonae compared to M. abscessus
[16]. These findings suggest that M. chelonae pulmonary infection may carry a better prognosis than M. abscessus although this remains somewhat speculative.
In the case we present, weight loss was the predominant feature although cough and dyspnea developed shortly after his initial presentation. The substantial and recurrent weight loss experienced by the patient we present highlights the importance of nutrition in NTM infections. Low body mass index (BMI) is a well established risk factor for NTM infection [17], [18]. Further, nutritional markers including low body weight, body fat and muscle mass have been correlated with an increased risk of progression of radiographic findings in M. avium complex infection [8], [9], [19]. Nonetheless, it is unclear whether weight loss represents a cause or effect of disease progression or indeed whether both are true. Further, to our knowledge the potential benefit of nutritional supplementation has not been evaluated.
In this case, the role played by nutritional supplementation cannot be definitively separated by that played by antibiotic therapy. The patient’s initial regimen of clarithromycin and moxifloxacin was insufficient as evidenced by his ongoing symptoms and positive sputum cultures despite 2 years of continuous therapy. However, the patient’s clinical status deteriorated even after escalation of antibiotic therapy and the initiation of percutaneous enteral feeding was co-incident with both weight gain and subsequent sputum conversion which suggests a probable benefit.
4 Conclusions
M. chelonae is a rare cause of pulmonary infection. Although optimal treatment regimens have not yet been fully established but a regimen of clarithromycin plus an additional antibiotic has been recommended. The prognosis of M. chelonae pulmonary infection also remains unclear but lower rates of macrolide resistance suggest that the prognosis may be better than the closely related species M. abscessus. Although its benefit has not been proven, nutrition supplementation, including percutaneous enteral feeding, can be considered for refractory NTM infection in underweight patients.
5 Ethics Statement
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33458256 | 19,221,460 | 2021-02 |
What was the outcome of reaction 'Alanine aminotransferase increased'? | A case of relapsed Mycobacterium chelonae pulmonary infection presenting with severe weight loss and treated with a combination of antibiotic therapy and percutaneous feeding.
Mycobacterium chelonae is a type of nontuberculous mycobacteria most commonly associated with skin and soft tissue infections. We present a case of recurrent M. chelonae pulmonary infection presenting with severe weight loss. After recurrence, sputum cultures remained positive for 2 years despite appropriate antibiotics. Cultures only became negative after the addition of intravenous imipenem and jejunostomy feeds. The rarity of M. chelonae pulmonary infection means that optimal treatment regimens have not yet been fully established but a regimen of clarithromycin plus an additional antibiotic has been recommended1. The prognosis of such infections also remains unclear but lower rates of macrolide resistance suggest that the prognosis may be better than the closely related species M. abscessus. Although its benefit has not been proven, nutrition supplementation, including percutaneous enteral feeding, can be considered for refractory NTM infection in underweight patients.
1 Introduction
Nontuberculous mycobacteria (NTM) include over 170 species [2]. Although not all species are pathogenic in humans, some are capable of causing potentially fatal pulmonary and extrapulmonary disease [1]. Further, the prevalence of NTM infections appears to be increasing across much of the world [3]. NTM are frequently classified into slowly-growing and rapidly-growing groups [1]. There are currently 3 main rapidly-growing mycobacterial (RGM) species of clinical importance: M. abcsessus, M. fortuitum and M. chelonae
[4]. M. chelonae most often causes skin and soft tissue infection which can also be a manifestation of disseminated disease [1]. Pulmonary infection has rarely been reported [5].
M. chelonae is commonly found in both natural bodies of water and municipal water supplies and water to is believed to be the usual source of human infection [6]. Risk factors for the development of NTM infection are numerous and include underlying lung disease, immune compromise and a tall slender body habitus especially when associated with pectus excavatum, scoliosis or mitral valve prolapse [7]. In recent years, malnourished status has also been recognized as a risk factor for disease progression in patients with NTM infection [8], [9] although it remains unclear if nutritional supplementation can alter patient outcomes.
We present a case of M. chelonae pulmonary infection successfully treated with a combination of antibiotic therapy and nutritional supplementation.
2 Case presentation
A 61 year-old man initially presented with unexplained weight loss of 9 kg over the preceding 12 months to a weight of 65 kg and a productive cough in June 2005. He had undergone a liver transplant in 2001 for hepatic cirrhosis in the context of hepatitis C infection and prior ethanol abuse. He had undergone a partial gastrectomy in the 1960 s for peptic ulcer disease. He is an ex-smoker with a 20 pack-year history who quit in 1992. During his assessment, he denied any recent dietary changes, night sweats or fevers. Tacrolimus was his only immunosuppressive medication and levels were therapeutic. A CT chest revealed mild bronchiectasis and nodules in the left lower lobe of the lung as well as nodules and patchy groundglass opacities in the right upper lobe (Fig. 1). A CT scan of the abdomen was unremarkable apart from evidence of his prior gastric surgery. A complete blood count, albumin, and bilirubin level were normal. Serum aminotransferases were elevated by approximately 2 times the upper limit of normal on initial assessment but normalized on repeat testing 6 weeks later. Testing for human immunodeficiency virus was negative.Fig. 1 Representitive image from a computed tomography of the chest of a patient with Mycobacterium chelonae pulmonary infection from June 2005. Notable findings in this imageare mild bronchiectasis and nodules in the left lower lobe of the lung.
Sputum cultures performed in September 2005 were positive for M. chelonae. The patient was initiated on rifampin 600 mg daily and clarithromycin 500 mg twice daily. With this therapy, his cough and exercise tolerance improved as did his radiographic abnormalities. Liver enzymes remained normal. By March 2006, he had regained 11 kg and his antibiotics were stopped. A repeat sputum culture was negative for mycobacteria in August 2007.
The patient was then lost to follow up until February 2010 when he presented with fever, cough and weight loss. His weigh had dropped 18.5 kg over at least 2 years and his BMI was 17.9. Repeat human immunodeficiency virus testing was negative. Esophagogastroduodenoscopy showed a small stomach with some retained food but he denied early satiety and regurgitation or symptoms of aspiration. He underwent nutritional counselling with the aim of increasing caloric intake. Two sputum cultures were again positive for M. chelonae.
He was started on moxifloxacin 400 mg daily and clarithromycin 500 mg twice daily in March 2010. Unfortunately, he remained febrile and continued to gradually lose weight. A repeat CT scan of chest revealed progression of bronchiectasis in comparison to 2005 as well as new groundglass opacities diffusely (Fig. 2). Despite therapy, repeat sputum cultures in March 2011 remained positive for M chelonae. Susceptibility testing revealed that the organism was sensitive to amikacin, imipenem and clarithromycin but resistant to ciprofloxacin, linezolid, cefoxitin and trimethoprim-sulfamethoxazole.Fig. 2 Computed tomography of the chest of a patient with recurrence of Mycobacterium chelonae pulmonary infection from June 2010. This image reveals progression of bronchiectasis in comparison to 2005 as well as new groundglass opacities.
He was referred to the mycobacterial disease clinic at our tertiary care centre in March 2012. His weight had fallen to 54.5 kg and sputum cultures were again positive for M. chelonae despite ongoing treatment with clarithromycin and moxifloxacin. His estimated glomerular filtration rate was 35 ml/min/1.73 m2 by diethylenetriaminepentaacetic acid renal scan. His poor renal function was felt to preclude the use of amikacin but imipenem 250 mg twice daily and doxycycline 100 mg twice daily were added to his regimen in April 2012. An elevation in alanine aminotransferase to 5 times the upper limit of normal prompted discontinuation of doxycycline in June 2012. Liver enzymes subsequently returned to baseline. Despite therapy, his weight had continued to decline to 52 kg by August 2012 and a jejunostomy tube was inserted. He received feeds consisting of Resource 2.0 (Nestle Health Science) at 40 cc/hour for 12 h per day in addition to food consumed orally.
With this therapy, his weight increased by 20 kg over 10 months and cough nearly resolved. Three mycobacterial sputum cultures were negative in November 2012 and again in April 2013. By October 2013, he was able to maintain a weight of 69.5 kg with jejunostomy tube feeds held so the tube was removed. Antibiotics were stopped in February 2014. Three mycobacterial sputum cultures were again negative in December 2014. Unfortunately, in May 2016, 1 of 3 sputum cultures was positive for M. chelonae and his weight had dropped to 60 kg. He felt well with no dyspnea and only minimal cough. He has had no progression of radiographic findings or symptoms. As such, he is being followed closely but therapy has not been re-initiated.
3 Discussion
Pulmonary infection with M. chelonae is rare. In a series from a Texas reference laboratory, 154 patients with pulmonary infection from RGM were identified over a 15-year period and only 1 patient was identified as having M. chelonae
[10]. Evaluation of previously published reports regarding M. chelonae is complicated by the evolving taxonomy of the species. Prior to 1992, M. chelonae was not recognized as a separate species from M. abscessus and even some studies published after this date do not differentiate between them [11]. However, differentiation between the two species is important due to differences in treatment and, most likely, prognosis [1], [10].
Given the rarity of the condition, optimal treatment for M. chelonae infection is not yet fully established. Recent guidelines for the treatment of NTM pulmonary disease do not offer specific recommendations for the treatment of this organism [12], [13]. However, previous guidelines suggest a combination of clarithromycin plus one of tobramycin, amikacin linezolid, imipenem, clofazimine, or doxycycline with selection of the additional antibiotic based on in vitro sensitivities [1]. Treatment is recommended to continue until 12 months of negative sputum cultures have been obtained [1].
It should be noted that initial management of the patient was not in keeping with these guidelines. Firstly, antibiotic susceptibility testing does was not performed initially and secondly rifampin is not typically part of recommended treatment [1]. Further, only 20% of M. chelonae isolates are susceptible to ciprofloxacin 20%, which likely translates to a low likelihood of susceptibility to moxifloxacin [1]. The rationale for these treatment decisions is unclear since they occurred prior to referral to our clinic.
In the present case, concerns regarding medication side effects (renal dysfunction and hepatotoxicity) also limited antibiotic options. This is common in the treatment of NTM infections with antibiotic discontinuation or dose reduction reported to occur 18–50% of the time in NTM infection [14].
However, even with optimal treatment, relapse of infection followed by persistent culture positivity despite prolonged antibiotics is common in the treatment of NTM and especially RGM [4]. Among RGM, treatment outcomes are best established for M. abscessus. Patients infected with macrolide-resistant strains of this organism are significantly less likely to achieve sputum culture conversion and relapse is nearly universal among those who do [15]. Macrolide resistance is less common and appears less likely to be induced in vitro by macrolide exposure in M. chelonae compared to M. abscessus
[16]. These findings suggest that M. chelonae pulmonary infection may carry a better prognosis than M. abscessus although this remains somewhat speculative.
In the case we present, weight loss was the predominant feature although cough and dyspnea developed shortly after his initial presentation. The substantial and recurrent weight loss experienced by the patient we present highlights the importance of nutrition in NTM infections. Low body mass index (BMI) is a well established risk factor for NTM infection [17], [18]. Further, nutritional markers including low body weight, body fat and muscle mass have been correlated with an increased risk of progression of radiographic findings in M. avium complex infection [8], [9], [19]. Nonetheless, it is unclear whether weight loss represents a cause or effect of disease progression or indeed whether both are true. Further, to our knowledge the potential benefit of nutritional supplementation has not been evaluated.
In this case, the role played by nutritional supplementation cannot be definitively separated by that played by antibiotic therapy. The patient’s initial regimen of clarithromycin and moxifloxacin was insufficient as evidenced by his ongoing symptoms and positive sputum cultures despite 2 years of continuous therapy. However, the patient’s clinical status deteriorated even after escalation of antibiotic therapy and the initiation of percutaneous enteral feeding was co-incident with both weight gain and subsequent sputum conversion which suggests a probable benefit.
4 Conclusions
M. chelonae is a rare cause of pulmonary infection. Although optimal treatment regimens have not yet been fully established but a regimen of clarithromycin plus an additional antibiotic has been recommended. The prognosis of M. chelonae pulmonary infection also remains unclear but lower rates of macrolide resistance suggest that the prognosis may be better than the closely related species M. abscessus. Although its benefit has not been proven, nutrition supplementation, including percutaneous enteral feeding, can be considered for refractory NTM infection in underweight patients.
5 Ethics Statement
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. | Recovered | ReactionOutcome | CC BY-NC-ND | 33458256 | 19,221,460 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Long-term remission of small cell lung cancer after reactivation of tuberculosis following immune-checkpoint blockade: A case report.
Immune-checkpoint inhibitors (ICIs) provide a promising treatment option for advanced tumors including small cell lung cancer (SCLC). Nevertheless, in addition to immune-related adverse events (irAEs), an increased risk of infection including tuberculosis has been previously described. Here, we report a case of long-term remission of a patient with SCLC after reactivation of lung tuberculosis following ICI therapy. Our case illustrates the complexity of ICI-associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.
INTRODUCTION
Small cell lung cancer (SCLC) is characterized by its high proliferative capacity and a high tendency to relapse after initial remission upon treatment with cytotoxic therapy. SCLC has a poor prognosis with a five‐year survival rate of only 7%.
1
SCLC is commonly associated with smoking and a subsequent high tumor mutational burden (TMB), as well as TP53 and retina blastoma protein (RB) mutations.
2
,
3
Although conventional platinum/etoposide‐based chemotherapy commonly results in striking tumor remissions, long‐term tumor control is a rare event.
4
Antibodies targeting the immune‐checkpoint molecules PD‐1/PDL‐1 and CTLA4 have shown promising results in SCLC.
5
,
6
In addition to immune‐related adverse events (irAEs), a known side effect of such therapies is the increased risk of infectious diseases including tuberculosis (TBC).
7
,
8
Here, we report on a rare case of a long‐term remission of a young SCLC patient after reactivation of lung tuberculosis following combined immune‐checkpoint blockade.
CASE REPORT
A 44‐year‐old man with a smoking history of 15 pack‐years was admitted to hospital complaining of recurrent episodes of cough and progressive dyspnoea. A diagnostic work‐up showed an extensive tumor mass in the right lung, originating from the upper lobe with infiltration of the middle and lower lobes. Histopathological analysis revealed the diagnosis of a small cell neuroendocrine tumor with a proliferation index (Ki67) of 80%. Upon confirmation of extensive disease stage (cT4, cN2, cMx), the patient underwent six cycles of palliative chemotherapy with cisplatinum/etoposide followed by radiotherapy of the primary tumor location with 42 Gy.
Twelve months after radiotherapy, the patient's general condition decreased rapidly and a computed tomography (CT) scan revealed a tumor relapse in the middle lobe of the right lung. A biopsy of the pulmonary lesion confirmed the diagnosis of the SCLC histopathologically. Genetic profiling was subsequently performed and showed a high mutational burden (up to 1166 missense variants), as well as alterations in TP53 (c.671_672insTTTGA, p.E224Dfs*25 and loss of wild‐type allele) and RB1 (c.2501C > G, p.S834*); two phenotypic mutations found in small cell cancers.
9
,
10
In addition, a BRCA1 (c.1529C > T; p.S510L and loss of wild‐type allele) mutation was identified. A second‐line therapy with the topoisomerase inhibitor topotecan failed after six cycles and resulted in a further progress of the central pulmonary tumor site (Figure 1a). Unfortunately, a cMRI‐scan revealed multiple cerebral lesions (Figure 1b). Radiotherapy to the brain (30 Gy) was concurrently administered. In consideration of the high mutational burden, combined immunotherapy with nivolumab and ipilimumab was initiated.
5
FIGURE 1 Clinical presentation of the SCLC patient and treatment scheme. (a) CT scan of the pulmonary SCLC lesion before and after ICI treatment. (b) Assessment of brain metastasis (white arrow) via cMRI prior to ICI treatment and after six months. (c) CT scan of the pulmonary MTB lesion before and after anti‐infective treatment. (d) Bronchoscopy of the primary MTB lesion in the left upper bronchus. (e) Neuron specific enolase (NSE) and CRP levels during the entire treatment (PD, progressive disease; SD, stable disease)
After three cycles of ICIs, a CT scan showed a relevant decrease in the central pulmonary mass (Figure 1a). However, a new lesion in the left and right upper lobe was demonstrated (Figure 1c). Laboratory tests showed elevated C‐reactive protein plasma levels (8–10 mg/dl, normal range up to 0.5 mg/dl) (Figure 1e). Interestingly, at this time, the patient presented with no clinical symptoms such as persistent cough or signs of clinical deterioration. Several enlarged mediastinal lymph nodes were associated with lymph node metastasis of the underlying SCLC. Bronchoscopy revealed a large cavity in the area of the left upper lobe connected to the bronchial system (Figure 1d). A Ziehl‐Neelsen (ZN) stain of the bronchoalveolar lavage showed a positive result for mycobacteria. In addition, a positive polymerase chain reaction of mycobacteria tuberculosis (MTB) was detected. Subsequently performed acid‐fast bacillus staining confirmed positive results in sputum samples and gastric lavage. Of note, a quantiferon test performed by a pneumologist prior to diagnosis of SCLC was negative. Susceptibility testing showed sensitivity to all tested antimycobacterial agents, beyond termination of ICI treatment, and a four‐drug combination of isoniazid, rifampicin, ethambutol, and pyrazinamide was commenced. After completion of this anti‐infective therapy, a relevant decrease in the size of both lung lesions was observed (Figure 1c), and the cerebral metastases were no longer detectable (Figure 1b).
Remarkably, without any further treatment, several CT scans showed no signs of tumor progression. To date, 24 months after the last treatment with ICIs, the patient shows a highly favorable physical condition as well as stable disease of all former detectable tumor manifestations.
DISCUSSION
The case presented here illustrates the concomitance of an active MTB infection upon ICI therapy and a prolonged remission of an advanced SCLC. Interestingly, reactivation of tuberculosis in cancer patients undergoing treatment with ICIs has been reported in a small number of cases.
7
In contrast to other infectious complications upon ICI treatment, which are commonly related to immune inhibitory treatment to control irAEs, exacerbation of MTB does not seem to be correlated with the use of corticosteroids or TNF inhibitors.
7
Even in our case, no irAE was detected or a subsequent immune inhibitory treatment administered. As a result, MTB reactivation might be directly correlated to ICI treatment. However, the underlying mechanisms triggering the reactivation in this context are only partially understood.
The role of T cells in MTB infections has been investigated in several preclinical models and showed that CD4+ T cells (Th1) play a major role in mycobacterial infections.
11
,
12
,
13
In contrast to data showing that blocking of PD‐1/PD‐L1 can partially prevent T cell exhaustion and subsequently restore T cell activity, lack of PD‐1 in MTB‐specific effector CD4+ T cells led to dysregulated IFN‐γ production and fatal immune‐mediated pathology.
14
In virus‐specific CD8+ T cells, PD‐1 knockdown (PD‐1−/−) led to a deeper T cell exhaustion compared to PD‐1 wild‐type.
15
In addition, PD‐1−/− mice had more severe and sometimes lethal causes of MTB infection.
12
,
16
These observations highlight the complex role of inhibitory immune‐checkpoint signaling mediating T cell exhaustion and immune surveillance during infections and cancer. Nevertheless, more data are urgently needed to better understand the particular role of ICI in MTB.
Our case, however not only describes a reactivation of MTB. We also observed a long‐term remission of the underlying tumor disease. Accordingly, the question arises whether the reactivation of MTB might additionally contribute to long‐term cancer immunosurveillance. It is known that TBC pathogens stimulate the activation of both innate and cellular immunity via different classes of cytokines.
17
Since mycobacteria associated antigens have also been described to enforce the antitumor immune response, a contribution of MTB to cancer immunosurveillance may be conceivable.
18
Hereby, it might be speculated that the exacerbation of MTB stimulated the host's immune response, thus leading to a reinforcement of the antitumor immune activity. This particular effect might be further enhanced after PD‐1/CTLA4 inhibition. However, more clinical and preclinical evidence is needed to prove such a hypothesis. Interestingly, an improved survival in non‐small cell lung cancer (NSCLC) patients affected by active tuberculosis compared to nonaffected NSCLC patients has already been described.
19
In summary, our case highlights the complex orchestra of immunomodulation in infection and cancer. Due to the fact that radiological signs of MTB including mediastinal or hilar lymphadenopathy, infiltrates, consolidations or cavities are commonly observed in lung cancer patients, diagnosis of MTB in lung cancer patients remains challenging. Moreover, since new lesions in lung cancer patients are commonly associated with tumor progression, MTB infections associated with ICIs might be underdiagnosed. As a consequence, specific testing for MTB in cancer patients receiving ICIs might be beneficial, even without strong clinical evidence.
In conclusion, this case report in a patient with long‐term remission of SCLC after infection with mycobacteria tuberculosis following immune‐checkpoint inhibitor (ICI) therapy emphasizes the need for further investigation of the complex crosstalk of ICI treatment, infection and cancer.
ACKNOWLEDGMENTS
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy ‐ EXC 2180–39090067. Open access funding enabled and organized by Projekt DEAL. | IPILIMUMAB, NIVOLUMAB, TOPOTECAN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33458956 | 19,192,311 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intentional product use issue'. | Long-term remission of small cell lung cancer after reactivation of tuberculosis following immune-checkpoint blockade: A case report.
Immune-checkpoint inhibitors (ICIs) provide a promising treatment option for advanced tumors including small cell lung cancer (SCLC). Nevertheless, in addition to immune-related adverse events (irAEs), an increased risk of infection including tuberculosis has been previously described. Here, we report a case of long-term remission of a patient with SCLC after reactivation of lung tuberculosis following ICI therapy. Our case illustrates the complexity of ICI-associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.
INTRODUCTION
Small cell lung cancer (SCLC) is characterized by its high proliferative capacity and a high tendency to relapse after initial remission upon treatment with cytotoxic therapy. SCLC has a poor prognosis with a five‐year survival rate of only 7%.
1
SCLC is commonly associated with smoking and a subsequent high tumor mutational burden (TMB), as well as TP53 and retina blastoma protein (RB) mutations.
2
,
3
Although conventional platinum/etoposide‐based chemotherapy commonly results in striking tumor remissions, long‐term tumor control is a rare event.
4
Antibodies targeting the immune‐checkpoint molecules PD‐1/PDL‐1 and CTLA4 have shown promising results in SCLC.
5
,
6
In addition to immune‐related adverse events (irAEs), a known side effect of such therapies is the increased risk of infectious diseases including tuberculosis (TBC).
7
,
8
Here, we report on a rare case of a long‐term remission of a young SCLC patient after reactivation of lung tuberculosis following combined immune‐checkpoint blockade.
CASE REPORT
A 44‐year‐old man with a smoking history of 15 pack‐years was admitted to hospital complaining of recurrent episodes of cough and progressive dyspnoea. A diagnostic work‐up showed an extensive tumor mass in the right lung, originating from the upper lobe with infiltration of the middle and lower lobes. Histopathological analysis revealed the diagnosis of a small cell neuroendocrine tumor with a proliferation index (Ki67) of 80%. Upon confirmation of extensive disease stage (cT4, cN2, cMx), the patient underwent six cycles of palliative chemotherapy with cisplatinum/etoposide followed by radiotherapy of the primary tumor location with 42 Gy.
Twelve months after radiotherapy, the patient's general condition decreased rapidly and a computed tomography (CT) scan revealed a tumor relapse in the middle lobe of the right lung. A biopsy of the pulmonary lesion confirmed the diagnosis of the SCLC histopathologically. Genetic profiling was subsequently performed and showed a high mutational burden (up to 1166 missense variants), as well as alterations in TP53 (c.671_672insTTTGA, p.E224Dfs*25 and loss of wild‐type allele) and RB1 (c.2501C > G, p.S834*); two phenotypic mutations found in small cell cancers.
9
,
10
In addition, a BRCA1 (c.1529C > T; p.S510L and loss of wild‐type allele) mutation was identified. A second‐line therapy with the topoisomerase inhibitor topotecan failed after six cycles and resulted in a further progress of the central pulmonary tumor site (Figure 1a). Unfortunately, a cMRI‐scan revealed multiple cerebral lesions (Figure 1b). Radiotherapy to the brain (30 Gy) was concurrently administered. In consideration of the high mutational burden, combined immunotherapy with nivolumab and ipilimumab was initiated.
5
FIGURE 1 Clinical presentation of the SCLC patient and treatment scheme. (a) CT scan of the pulmonary SCLC lesion before and after ICI treatment. (b) Assessment of brain metastasis (white arrow) via cMRI prior to ICI treatment and after six months. (c) CT scan of the pulmonary MTB lesion before and after anti‐infective treatment. (d) Bronchoscopy of the primary MTB lesion in the left upper bronchus. (e) Neuron specific enolase (NSE) and CRP levels during the entire treatment (PD, progressive disease; SD, stable disease)
After three cycles of ICIs, a CT scan showed a relevant decrease in the central pulmonary mass (Figure 1a). However, a new lesion in the left and right upper lobe was demonstrated (Figure 1c). Laboratory tests showed elevated C‐reactive protein plasma levels (8–10 mg/dl, normal range up to 0.5 mg/dl) (Figure 1e). Interestingly, at this time, the patient presented with no clinical symptoms such as persistent cough or signs of clinical deterioration. Several enlarged mediastinal lymph nodes were associated with lymph node metastasis of the underlying SCLC. Bronchoscopy revealed a large cavity in the area of the left upper lobe connected to the bronchial system (Figure 1d). A Ziehl‐Neelsen (ZN) stain of the bronchoalveolar lavage showed a positive result for mycobacteria. In addition, a positive polymerase chain reaction of mycobacteria tuberculosis (MTB) was detected. Subsequently performed acid‐fast bacillus staining confirmed positive results in sputum samples and gastric lavage. Of note, a quantiferon test performed by a pneumologist prior to diagnosis of SCLC was negative. Susceptibility testing showed sensitivity to all tested antimycobacterial agents, beyond termination of ICI treatment, and a four‐drug combination of isoniazid, rifampicin, ethambutol, and pyrazinamide was commenced. After completion of this anti‐infective therapy, a relevant decrease in the size of both lung lesions was observed (Figure 1c), and the cerebral metastases were no longer detectable (Figure 1b).
Remarkably, without any further treatment, several CT scans showed no signs of tumor progression. To date, 24 months after the last treatment with ICIs, the patient shows a highly favorable physical condition as well as stable disease of all former detectable tumor manifestations.
DISCUSSION
The case presented here illustrates the concomitance of an active MTB infection upon ICI therapy and a prolonged remission of an advanced SCLC. Interestingly, reactivation of tuberculosis in cancer patients undergoing treatment with ICIs has been reported in a small number of cases.
7
In contrast to other infectious complications upon ICI treatment, which are commonly related to immune inhibitory treatment to control irAEs, exacerbation of MTB does not seem to be correlated with the use of corticosteroids or TNF inhibitors.
7
Even in our case, no irAE was detected or a subsequent immune inhibitory treatment administered. As a result, MTB reactivation might be directly correlated to ICI treatment. However, the underlying mechanisms triggering the reactivation in this context are only partially understood.
The role of T cells in MTB infections has been investigated in several preclinical models and showed that CD4+ T cells (Th1) play a major role in mycobacterial infections.
11
,
12
,
13
In contrast to data showing that blocking of PD‐1/PD‐L1 can partially prevent T cell exhaustion and subsequently restore T cell activity, lack of PD‐1 in MTB‐specific effector CD4+ T cells led to dysregulated IFN‐γ production and fatal immune‐mediated pathology.
14
In virus‐specific CD8+ T cells, PD‐1 knockdown (PD‐1−/−) led to a deeper T cell exhaustion compared to PD‐1 wild‐type.
15
In addition, PD‐1−/− mice had more severe and sometimes lethal causes of MTB infection.
12
,
16
These observations highlight the complex role of inhibitory immune‐checkpoint signaling mediating T cell exhaustion and immune surveillance during infections and cancer. Nevertheless, more data are urgently needed to better understand the particular role of ICI in MTB.
Our case, however not only describes a reactivation of MTB. We also observed a long‐term remission of the underlying tumor disease. Accordingly, the question arises whether the reactivation of MTB might additionally contribute to long‐term cancer immunosurveillance. It is known that TBC pathogens stimulate the activation of both innate and cellular immunity via different classes of cytokines.
17
Since mycobacteria associated antigens have also been described to enforce the antitumor immune response, a contribution of MTB to cancer immunosurveillance may be conceivable.
18
Hereby, it might be speculated that the exacerbation of MTB stimulated the host's immune response, thus leading to a reinforcement of the antitumor immune activity. This particular effect might be further enhanced after PD‐1/CTLA4 inhibition. However, more clinical and preclinical evidence is needed to prove such a hypothesis. Interestingly, an improved survival in non‐small cell lung cancer (NSCLC) patients affected by active tuberculosis compared to nonaffected NSCLC patients has already been described.
19
In summary, our case highlights the complex orchestra of immunomodulation in infection and cancer. Due to the fact that radiological signs of MTB including mediastinal or hilar lymphadenopathy, infiltrates, consolidations or cavities are commonly observed in lung cancer patients, diagnosis of MTB in lung cancer patients remains challenging. Moreover, since new lesions in lung cancer patients are commonly associated with tumor progression, MTB infections associated with ICIs might be underdiagnosed. As a consequence, specific testing for MTB in cancer patients receiving ICIs might be beneficial, even without strong clinical evidence.
In conclusion, this case report in a patient with long‐term remission of SCLC after infection with mycobacteria tuberculosis following immune‐checkpoint inhibitor (ICI) therapy emphasizes the need for further investigation of the complex crosstalk of ICI treatment, infection and cancer.
ACKNOWLEDGMENTS
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy ‐ EXC 2180–39090067. Open access funding enabled and organized by Projekt DEAL. | IPILIMUMAB, NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33458956 | 18,833,826 | 2021-03 |
What was the dosage of drug 'TOPOTECAN HYDROCHLORIDE'? | Long-term remission of small cell lung cancer after reactivation of tuberculosis following immune-checkpoint blockade: A case report.
Immune-checkpoint inhibitors (ICIs) provide a promising treatment option for advanced tumors including small cell lung cancer (SCLC). Nevertheless, in addition to immune-related adverse events (irAEs), an increased risk of infection including tuberculosis has been previously described. Here, we report a case of long-term remission of a patient with SCLC after reactivation of lung tuberculosis following ICI therapy. Our case illustrates the complexity of ICI-associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.
INTRODUCTION
Small cell lung cancer (SCLC) is characterized by its high proliferative capacity and a high tendency to relapse after initial remission upon treatment with cytotoxic therapy. SCLC has a poor prognosis with a five‐year survival rate of only 7%.
1
SCLC is commonly associated with smoking and a subsequent high tumor mutational burden (TMB), as well as TP53 and retina blastoma protein (RB) mutations.
2
,
3
Although conventional platinum/etoposide‐based chemotherapy commonly results in striking tumor remissions, long‐term tumor control is a rare event.
4
Antibodies targeting the immune‐checkpoint molecules PD‐1/PDL‐1 and CTLA4 have shown promising results in SCLC.
5
,
6
In addition to immune‐related adverse events (irAEs), a known side effect of such therapies is the increased risk of infectious diseases including tuberculosis (TBC).
7
,
8
Here, we report on a rare case of a long‐term remission of a young SCLC patient after reactivation of lung tuberculosis following combined immune‐checkpoint blockade.
CASE REPORT
A 44‐year‐old man with a smoking history of 15 pack‐years was admitted to hospital complaining of recurrent episodes of cough and progressive dyspnoea. A diagnostic work‐up showed an extensive tumor mass in the right lung, originating from the upper lobe with infiltration of the middle and lower lobes. Histopathological analysis revealed the diagnosis of a small cell neuroendocrine tumor with a proliferation index (Ki67) of 80%. Upon confirmation of extensive disease stage (cT4, cN2, cMx), the patient underwent six cycles of palliative chemotherapy with cisplatinum/etoposide followed by radiotherapy of the primary tumor location with 42 Gy.
Twelve months after radiotherapy, the patient's general condition decreased rapidly and a computed tomography (CT) scan revealed a tumor relapse in the middle lobe of the right lung. A biopsy of the pulmonary lesion confirmed the diagnosis of the SCLC histopathologically. Genetic profiling was subsequently performed and showed a high mutational burden (up to 1166 missense variants), as well as alterations in TP53 (c.671_672insTTTGA, p.E224Dfs*25 and loss of wild‐type allele) and RB1 (c.2501C > G, p.S834*); two phenotypic mutations found in small cell cancers.
9
,
10
In addition, a BRCA1 (c.1529C > T; p.S510L and loss of wild‐type allele) mutation was identified. A second‐line therapy with the topoisomerase inhibitor topotecan failed after six cycles and resulted in a further progress of the central pulmonary tumor site (Figure 1a). Unfortunately, a cMRI‐scan revealed multiple cerebral lesions (Figure 1b). Radiotherapy to the brain (30 Gy) was concurrently administered. In consideration of the high mutational burden, combined immunotherapy with nivolumab and ipilimumab was initiated.
5
FIGURE 1 Clinical presentation of the SCLC patient and treatment scheme. (a) CT scan of the pulmonary SCLC lesion before and after ICI treatment. (b) Assessment of brain metastasis (white arrow) via cMRI prior to ICI treatment and after six months. (c) CT scan of the pulmonary MTB lesion before and after anti‐infective treatment. (d) Bronchoscopy of the primary MTB lesion in the left upper bronchus. (e) Neuron specific enolase (NSE) and CRP levels during the entire treatment (PD, progressive disease; SD, stable disease)
After three cycles of ICIs, a CT scan showed a relevant decrease in the central pulmonary mass (Figure 1a). However, a new lesion in the left and right upper lobe was demonstrated (Figure 1c). Laboratory tests showed elevated C‐reactive protein plasma levels (8–10 mg/dl, normal range up to 0.5 mg/dl) (Figure 1e). Interestingly, at this time, the patient presented with no clinical symptoms such as persistent cough or signs of clinical deterioration. Several enlarged mediastinal lymph nodes were associated with lymph node metastasis of the underlying SCLC. Bronchoscopy revealed a large cavity in the area of the left upper lobe connected to the bronchial system (Figure 1d). A Ziehl‐Neelsen (ZN) stain of the bronchoalveolar lavage showed a positive result for mycobacteria. In addition, a positive polymerase chain reaction of mycobacteria tuberculosis (MTB) was detected. Subsequently performed acid‐fast bacillus staining confirmed positive results in sputum samples and gastric lavage. Of note, a quantiferon test performed by a pneumologist prior to diagnosis of SCLC was negative. Susceptibility testing showed sensitivity to all tested antimycobacterial agents, beyond termination of ICI treatment, and a four‐drug combination of isoniazid, rifampicin, ethambutol, and pyrazinamide was commenced. After completion of this anti‐infective therapy, a relevant decrease in the size of both lung lesions was observed (Figure 1c), and the cerebral metastases were no longer detectable (Figure 1b).
Remarkably, without any further treatment, several CT scans showed no signs of tumor progression. To date, 24 months after the last treatment with ICIs, the patient shows a highly favorable physical condition as well as stable disease of all former detectable tumor manifestations.
DISCUSSION
The case presented here illustrates the concomitance of an active MTB infection upon ICI therapy and a prolonged remission of an advanced SCLC. Interestingly, reactivation of tuberculosis in cancer patients undergoing treatment with ICIs has been reported in a small number of cases.
7
In contrast to other infectious complications upon ICI treatment, which are commonly related to immune inhibitory treatment to control irAEs, exacerbation of MTB does not seem to be correlated with the use of corticosteroids or TNF inhibitors.
7
Even in our case, no irAE was detected or a subsequent immune inhibitory treatment administered. As a result, MTB reactivation might be directly correlated to ICI treatment. However, the underlying mechanisms triggering the reactivation in this context are only partially understood.
The role of T cells in MTB infections has been investigated in several preclinical models and showed that CD4+ T cells (Th1) play a major role in mycobacterial infections.
11
,
12
,
13
In contrast to data showing that blocking of PD‐1/PD‐L1 can partially prevent T cell exhaustion and subsequently restore T cell activity, lack of PD‐1 in MTB‐specific effector CD4+ T cells led to dysregulated IFN‐γ production and fatal immune‐mediated pathology.
14
In virus‐specific CD8+ T cells, PD‐1 knockdown (PD‐1−/−) led to a deeper T cell exhaustion compared to PD‐1 wild‐type.
15
In addition, PD‐1−/− mice had more severe and sometimes lethal causes of MTB infection.
12
,
16
These observations highlight the complex role of inhibitory immune‐checkpoint signaling mediating T cell exhaustion and immune surveillance during infections and cancer. Nevertheless, more data are urgently needed to better understand the particular role of ICI in MTB.
Our case, however not only describes a reactivation of MTB. We also observed a long‐term remission of the underlying tumor disease. Accordingly, the question arises whether the reactivation of MTB might additionally contribute to long‐term cancer immunosurveillance. It is known that TBC pathogens stimulate the activation of both innate and cellular immunity via different classes of cytokines.
17
Since mycobacteria associated antigens have also been described to enforce the antitumor immune response, a contribution of MTB to cancer immunosurveillance may be conceivable.
18
Hereby, it might be speculated that the exacerbation of MTB stimulated the host's immune response, thus leading to a reinforcement of the antitumor immune activity. This particular effect might be further enhanced after PD‐1/CTLA4 inhibition. However, more clinical and preclinical evidence is needed to prove such a hypothesis. Interestingly, an improved survival in non‐small cell lung cancer (NSCLC) patients affected by active tuberculosis compared to nonaffected NSCLC patients has already been described.
19
In summary, our case highlights the complex orchestra of immunomodulation in infection and cancer. Due to the fact that radiological signs of MTB including mediastinal or hilar lymphadenopathy, infiltrates, consolidations or cavities are commonly observed in lung cancer patients, diagnosis of MTB in lung cancer patients remains challenging. Moreover, since new lesions in lung cancer patients are commonly associated with tumor progression, MTB infections associated with ICIs might be underdiagnosed. As a consequence, specific testing for MTB in cancer patients receiving ICIs might be beneficial, even without strong clinical evidence.
In conclusion, this case report in a patient with long‐term remission of SCLC after infection with mycobacteria tuberculosis following immune‐checkpoint inhibitor (ICI) therapy emphasizes the need for further investigation of the complex crosstalk of ICI treatment, infection and cancer.
ACKNOWLEDGMENTS
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy ‐ EXC 2180–39090067. Open access funding enabled and organized by Projekt DEAL. | NO RESPONSE NOTED AFTER 6 CYCLES | DrugDosageText | CC BY-NC-ND | 33458956 | 19,192,311 | 2021-03 |
What was the outcome of reaction 'Tuberculosis'? | Long-term remission of small cell lung cancer after reactivation of tuberculosis following immune-checkpoint blockade: A case report.
Immune-checkpoint inhibitors (ICIs) provide a promising treatment option for advanced tumors including small cell lung cancer (SCLC). Nevertheless, in addition to immune-related adverse events (irAEs), an increased risk of infection including tuberculosis has been previously described. Here, we report a case of long-term remission of a patient with SCLC after reactivation of lung tuberculosis following ICI therapy. Our case illustrates the complexity of ICI-associated immune modulation in tuberculosis. Since new lesions in lung cancer patients are commonly associated with tumor progression, infections with mycobacterial tuberculosis may be underdiagnosed in lung cancer.
INTRODUCTION
Small cell lung cancer (SCLC) is characterized by its high proliferative capacity and a high tendency to relapse after initial remission upon treatment with cytotoxic therapy. SCLC has a poor prognosis with a five‐year survival rate of only 7%.
1
SCLC is commonly associated with smoking and a subsequent high tumor mutational burden (TMB), as well as TP53 and retina blastoma protein (RB) mutations.
2
,
3
Although conventional platinum/etoposide‐based chemotherapy commonly results in striking tumor remissions, long‐term tumor control is a rare event.
4
Antibodies targeting the immune‐checkpoint molecules PD‐1/PDL‐1 and CTLA4 have shown promising results in SCLC.
5
,
6
In addition to immune‐related adverse events (irAEs), a known side effect of such therapies is the increased risk of infectious diseases including tuberculosis (TBC).
7
,
8
Here, we report on a rare case of a long‐term remission of a young SCLC patient after reactivation of lung tuberculosis following combined immune‐checkpoint blockade.
CASE REPORT
A 44‐year‐old man with a smoking history of 15 pack‐years was admitted to hospital complaining of recurrent episodes of cough and progressive dyspnoea. A diagnostic work‐up showed an extensive tumor mass in the right lung, originating from the upper lobe with infiltration of the middle and lower lobes. Histopathological analysis revealed the diagnosis of a small cell neuroendocrine tumor with a proliferation index (Ki67) of 80%. Upon confirmation of extensive disease stage (cT4, cN2, cMx), the patient underwent six cycles of palliative chemotherapy with cisplatinum/etoposide followed by radiotherapy of the primary tumor location with 42 Gy.
Twelve months after radiotherapy, the patient's general condition decreased rapidly and a computed tomography (CT) scan revealed a tumor relapse in the middle lobe of the right lung. A biopsy of the pulmonary lesion confirmed the diagnosis of the SCLC histopathologically. Genetic profiling was subsequently performed and showed a high mutational burden (up to 1166 missense variants), as well as alterations in TP53 (c.671_672insTTTGA, p.E224Dfs*25 and loss of wild‐type allele) and RB1 (c.2501C > G, p.S834*); two phenotypic mutations found in small cell cancers.
9
,
10
In addition, a BRCA1 (c.1529C > T; p.S510L and loss of wild‐type allele) mutation was identified. A second‐line therapy with the topoisomerase inhibitor topotecan failed after six cycles and resulted in a further progress of the central pulmonary tumor site (Figure 1a). Unfortunately, a cMRI‐scan revealed multiple cerebral lesions (Figure 1b). Radiotherapy to the brain (30 Gy) was concurrently administered. In consideration of the high mutational burden, combined immunotherapy with nivolumab and ipilimumab was initiated.
5
FIGURE 1 Clinical presentation of the SCLC patient and treatment scheme. (a) CT scan of the pulmonary SCLC lesion before and after ICI treatment. (b) Assessment of brain metastasis (white arrow) via cMRI prior to ICI treatment and after six months. (c) CT scan of the pulmonary MTB lesion before and after anti‐infective treatment. (d) Bronchoscopy of the primary MTB lesion in the left upper bronchus. (e) Neuron specific enolase (NSE) and CRP levels during the entire treatment (PD, progressive disease; SD, stable disease)
After three cycles of ICIs, a CT scan showed a relevant decrease in the central pulmonary mass (Figure 1a). However, a new lesion in the left and right upper lobe was demonstrated (Figure 1c). Laboratory tests showed elevated C‐reactive protein plasma levels (8–10 mg/dl, normal range up to 0.5 mg/dl) (Figure 1e). Interestingly, at this time, the patient presented with no clinical symptoms such as persistent cough or signs of clinical deterioration. Several enlarged mediastinal lymph nodes were associated with lymph node metastasis of the underlying SCLC. Bronchoscopy revealed a large cavity in the area of the left upper lobe connected to the bronchial system (Figure 1d). A Ziehl‐Neelsen (ZN) stain of the bronchoalveolar lavage showed a positive result for mycobacteria. In addition, a positive polymerase chain reaction of mycobacteria tuberculosis (MTB) was detected. Subsequently performed acid‐fast bacillus staining confirmed positive results in sputum samples and gastric lavage. Of note, a quantiferon test performed by a pneumologist prior to diagnosis of SCLC was negative. Susceptibility testing showed sensitivity to all tested antimycobacterial agents, beyond termination of ICI treatment, and a four‐drug combination of isoniazid, rifampicin, ethambutol, and pyrazinamide was commenced. After completion of this anti‐infective therapy, a relevant decrease in the size of both lung lesions was observed (Figure 1c), and the cerebral metastases were no longer detectable (Figure 1b).
Remarkably, without any further treatment, several CT scans showed no signs of tumor progression. To date, 24 months after the last treatment with ICIs, the patient shows a highly favorable physical condition as well as stable disease of all former detectable tumor manifestations.
DISCUSSION
The case presented here illustrates the concomitance of an active MTB infection upon ICI therapy and a prolonged remission of an advanced SCLC. Interestingly, reactivation of tuberculosis in cancer patients undergoing treatment with ICIs has been reported in a small number of cases.
7
In contrast to other infectious complications upon ICI treatment, which are commonly related to immune inhibitory treatment to control irAEs, exacerbation of MTB does not seem to be correlated with the use of corticosteroids or TNF inhibitors.
7
Even in our case, no irAE was detected or a subsequent immune inhibitory treatment administered. As a result, MTB reactivation might be directly correlated to ICI treatment. However, the underlying mechanisms triggering the reactivation in this context are only partially understood.
The role of T cells in MTB infections has been investigated in several preclinical models and showed that CD4+ T cells (Th1) play a major role in mycobacterial infections.
11
,
12
,
13
In contrast to data showing that blocking of PD‐1/PD‐L1 can partially prevent T cell exhaustion and subsequently restore T cell activity, lack of PD‐1 in MTB‐specific effector CD4+ T cells led to dysregulated IFN‐γ production and fatal immune‐mediated pathology.
14
In virus‐specific CD8+ T cells, PD‐1 knockdown (PD‐1−/−) led to a deeper T cell exhaustion compared to PD‐1 wild‐type.
15
In addition, PD‐1−/− mice had more severe and sometimes lethal causes of MTB infection.
12
,
16
These observations highlight the complex role of inhibitory immune‐checkpoint signaling mediating T cell exhaustion and immune surveillance during infections and cancer. Nevertheless, more data are urgently needed to better understand the particular role of ICI in MTB.
Our case, however not only describes a reactivation of MTB. We also observed a long‐term remission of the underlying tumor disease. Accordingly, the question arises whether the reactivation of MTB might additionally contribute to long‐term cancer immunosurveillance. It is known that TBC pathogens stimulate the activation of both innate and cellular immunity via different classes of cytokines.
17
Since mycobacteria associated antigens have also been described to enforce the antitumor immune response, a contribution of MTB to cancer immunosurveillance may be conceivable.
18
Hereby, it might be speculated that the exacerbation of MTB stimulated the host's immune response, thus leading to a reinforcement of the antitumor immune activity. This particular effect might be further enhanced after PD‐1/CTLA4 inhibition. However, more clinical and preclinical evidence is needed to prove such a hypothesis. Interestingly, an improved survival in non‐small cell lung cancer (NSCLC) patients affected by active tuberculosis compared to nonaffected NSCLC patients has already been described.
19
In summary, our case highlights the complex orchestra of immunomodulation in infection and cancer. Due to the fact that radiological signs of MTB including mediastinal or hilar lymphadenopathy, infiltrates, consolidations or cavities are commonly observed in lung cancer patients, diagnosis of MTB in lung cancer patients remains challenging. Moreover, since new lesions in lung cancer patients are commonly associated with tumor progression, MTB infections associated with ICIs might be underdiagnosed. As a consequence, specific testing for MTB in cancer patients receiving ICIs might be beneficial, even without strong clinical evidence.
In conclusion, this case report in a patient with long‐term remission of SCLC after infection with mycobacteria tuberculosis following immune‐checkpoint inhibitor (ICI) therapy emphasizes the need for further investigation of the complex crosstalk of ICI treatment, infection and cancer.
ACKNOWLEDGMENTS
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy ‐ EXC 2180–39090067. Open access funding enabled and organized by Projekt DEAL. | Recovering | ReactionOutcome | CC BY-NC-ND | 33458956 | 18,833,826 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adrenal insufficiency'. | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | DOCETAXEL, NIVOLUMAB, RAMUCIRUMAB | DrugsGivenReaction | CC BY-NC | 33459466 | 19,699,791 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pleural effusion'. | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | DOCETAXEL, NIVOLUMAB, RAMUCIRUMAB | DrugsGivenReaction | CC BY-NC | 33459466 | 19,699,791 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Prescribed overdose'. | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | BETAMETHASONE, ESOMEPRAZOLE MAGNESIUM, LEVETIRACETAM, NIVOLUMAB | DrugsGivenReaction | CC BY-NC | 33459466 | 19,700,745 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thyroid disorder'. | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | DOCETAXEL, NIVOLUMAB, RAMUCIRUMAB | DrugsGivenReaction | CC BY-NC | 33459466 | 19,699,791 | 2021-03 |
What is the weight of the patient? | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | 44 kg. | Weight | CC BY-NC | 33459466 | 19,700,745 | 2021-03 |
What was the administration route of drug 'BETAMETHASONE'? | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY-NC | 33459466 | 19,700,745 | 2021-03 |
What was the administration route of drug 'ESOMEPRAZOLE MAGNESIUM'? | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY-NC | 33459466 | 19,700,745 | 2021-03 |
What was the administration route of drug 'IPILIMUMAB'? | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | Intravenous drip | DrugAdministrationRoute | CC BY-NC | 33459466 | 19,158,392 | 2021-03 |
What was the administration route of drug 'LEVETIRACETAM'? | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY-NC | 33459466 | 19,700,745 | 2021-03 |
What was the administration route of drug 'NIVOLUMAB'? | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | Intravenous drip | DrugAdministrationRoute | CC BY-NC | 33459466 | 19,159,097 | 2021-03 |
What was the dosage of drug 'IPILIMUMAB'? | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | 1 MILLIGRAM/KILOGRAM, Q3WK | DrugDosageText | CC BY-NC | 33459466 | 19,158,392 | 2021-03 |
What was the outcome of reaction 'Adrenal insufficiency'? | Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis.
Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.
1 BACKGROUND
The increasing adoption of cancer immunotherapy with immune checkpoint inhibitors (ICIs) has given us an additional therapeutic option for various types of malignant tumors. However, the considerable success of ICIs has unfortunately increased immune‐related adverse events (irAEs). 1 Enterocolitis is a relatively frequent irAE, particularly in patients treated with ipilimumab, an anticytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody. Diarrhea occurs in 12%‐13% of patients administered antiprogrammed death receptor‐1 (PD‐1), 30%‐35% of those administered anti‐CTLA‐4, and 10% of those treated with combination therapy. 2 Because irAEs greatly reduce quality of life and often show a clinical course different from that of ordinary autoimmune diseases, their appropriate diagnosis and treatment are important subjects. Based on our current understanding, irAE‐associated enterocolitis does not show specific histological findings—any type of inflammation can be found. 2 , 3
As described in this brief report, we investigated the histopathology of colon tissue from patients treated with ICIs. Interestingly, we discovered a characteristic feature that was a specific finding for the colon after treatment with ICIs. In addition, the theoretical mechanism of this feature would be consistent with efficient cancer immunity. In other words, this novel feature could be a potential surrogate marker of systemic anticancer immune activation.
2 METHODS
2.1 Patients and specimens
With approval of the institutional review board (322‐134: Clinicopathological investigation of irAE caused by immune checkpoint inhibitors), the formalin‐fixed, paraffin‐embedded material archives of Sapporo Medical University Hospital, Hakodate Goryoukaku Hospital, Sunagawa City Medical Center, Asahikawa Red Cross Hospital, Otaru City General Hospital, and Kushiro City General Hospital were searched for colorectal biopsy or surgical resection specimens from patients administered ICIs. Informed consent was obtained through an opt‐out on the website according to the guidelines of the Declaration of Helsinki. A total of 17 specimens were available: 16 were biopsies and one was a surgical resection specimen that was independent of the primary tumor. Patient histories were examined for relevant clinicopathological factors, including age, sex, primary tumor, type of ICI, intestinal symptoms, endoscopic findings, and other irAEs. The clinical effects of ICIs were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria. In each evaluation, the best clinical response before intestinal symptoms was analyzed. To obtain concordant results regarding the histological analysis, each slide was examined on a multiheaded microscope by three pathologists.
2.2 IHC staining
Tumor tissues were fixed in 10% buffered formalin and embedded in paraffin. Sections (4 μm thick) of formalin‐fixed paraffin‐embedded tumor tissues were stained with the following monoclonal antibodies after epitope retrieval using Target Retrieval Solution pH 9 (DAKO): mouse anti‐CD4 monoclonal antibody (clone 4B12; Thermo Fisher Scientific), mouse anti‐CD8 monoclonal antibody (clone C8/144B; DAKO), and mouse anti‐CD68 monoclonal antibody (clone PG‐M1; Nichirei Biosciences). These antibodies were used according to the manufacturers’ instructions.
3 RESULTS
3.1 Patient characteristics
We analyzed colon tissue samples from 17 patients treated with ICIs. Clinicopathological and histopathological features are summarized in Table 1. The patients comprised eight men and nine women with a median age of 69 (range, 58‐86) years. Six were receiving ICIs for lung adenocarcinoma, three had lung squamous cell carcinoma, three had urothelial carcinoma of the urinary bladder, two had malignant melanoma, and one each had lung carcinosarcoma, renal tumor (no histological confirmation was performed), and mucoepidermoid carcinoma. Most patients underwent chemoradiotherapy before treatment with ICIs (data not shown). Nine patients were administered pembrolizumab and six received nivolumab. One patient received atezolizumab and one received a combination of ipilimumab and nivolumab. In response to ICIs, five patients had progressive disease, whereas the others had disease control (complete response, six patients; partial response, five; stable disease, two). No patient had a history of inflammatory bowel disease, including ulcerative colitis (UC) or Crohn's disease.
TABLE 1 Clinicopathological features of the 17 patients treated with ICIs
Age (years) Sex Tumor Type of ICI (cycles) Effect Symptom Endoscopic finding Histology SSG Other irAE
1 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (8) PR Diarrhea Nonspecific GVHD‐like Positive No
2 66 M Lung adeno Ca Nivolumab: 170 mg/2 wk (3) PD Diarrhea Normal UC‐like Negative No
3 55 M Lung adeno Ca Nivolumab: 150 mg/2 wk (11) PD Diarrhea Nonspecific Nonspecific Negative No
4 69 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PD Diarrhea Nonspecific UC‐like Negative No
5 70 M Lung adeno Ca Pembrolizumab: 200 mg/3 wk (16) PR Diarrhea UC‐like UC‐like Positive Uveitis
6 67 F Lung adeno Ca Pembrolizumab: 200 mg (1) PR Diarrhea, Melena UC‐like Nonspecific Negative No
7 86 F Lung SCC Nivolumab :155 mg/2 wk (5), 240 mg/2 wk (17) SD Diarrhea Nonspecific GVHD‐like Negative No
8 58 F Lung SCC Atezolizumab: 1200 mg/3 wk (10) SD Diarrhea, melena UC‐like UC‐like Positive No
9 71 M Lung SCC Pembrolizumab: 200 mg/3 wk (3) PR None Normal None Positive No
10 69 F Lung carcinosarcoma Pembrolizumab: 200 mg/3 wk (1) PD Melena Nonspecific UC‐like Negative No
11 66 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (11) CR Diarrhea UC‐like UC‐like Positive No
12 77 F Urothelial Ca Pembrolizumab: 200 mg/3 wk (10) PR Diarrhea Normal GVHD‐like Positive No
13 63 M Urothelial Ca Pembrolizumab: 200 mg/3 wk (15) CR Melena Ischemic Nonspecific Negative No
14 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (6) CR Diarrhea, melena UC‐like UC‐like Positive No
15 74 F Melanoma Nivolumab: 3 mg/kg/2 wk (3) PD Diarrhea Nonspecific GVHD‐like Positive No
16 64 F Renal tumor Ipilimumab:1 mg/kg + Nivolumab: 240 mg/3 wk (4) CR Abdominal pain Normal GVHD‐like Positive No
17 67 F Mucoepidermoid Ca Nivolumab: 240 mg/3 wk (4) PR Diarrhea Normal GVHD‐like Positive Dermatitis
Abbreviations: Ca, carcinoma; CR, complete response; GVHD, graft vs host disease; ICI, immune checkpoint inhibitor; irAE, immune‐related adverse event; PR, partial response; SCC, squamous cell carcinoma; SD, stable disease; SSG, subepithelial surface granulomatosis; UC, ulcerative colitis.
John Wiley & Sons, Ltd
3.2 Clinical presentation and endoscopic findings
The most common symptom was diarrhea, reported by 13 of the 17 patients. Five patients had melena and one had abdominal pain. One patient had uveitis and one had dermatitis in addition to intestinal symptoms. Colonoscopy findings were typical for nonspecific colitis and UC‐like severe inflammation. There was no tendency for a frequent inflamed region between the rectum and cecum.
3.3 Histopathological findings
There were two major histological patterns of colitis: an UC‐like pattern or a graft vs host disease (GVHD)‐like pattern (Figure 1A). Remarkable crypt atrophy or distortion, implying chronic inflammation, was not clear in either pattern. The UC‐like pattern exhibited an increased number of neutrophil and frequent cryptitis and/or crypt abscess. On the other hand, lymphocyte infiltration into the epithelium and occasional apoptotic bodies were characteristic findings in the GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells were CD8 positive, whereas CD4‐positive cells were located in interstitial lesions of the lamina propria (Figure 1B). We could not find statistically significant difference in clinical effect of ICIs between these two groups (P = .27, Fisher's exact test).
FIGURE 1 Histopathological images of the two patterns of immune‐related adverse event (irAE)‐associated enterocolitis. A, Two major histological patterns of irAE‐associated enterocolitis. Left panel: ulcerative colitis (UC)‐like pattern. Arrows and the arrowhead indicate crypt abscesses and cryptitis, respectively. Right panel: graft vs host disease (GVHD)‐like pattern. Arrows and the arrowhead indicate lymphocyte infiltrates and an apoptotic body, respectively. Bar = 50 μm. B, Lymphocyte subtypes in GVHD‐like pattern. Lymphocytes infiltrating into epithelial cells are CD8 positive (arrows), whereas CD4‐positive cells are located in the interstitial region. Bar = 50 μm
Interestingly, nine of the 17 patients showed a characteristic mucosal lesion involving subepithelial aggregation of cells with occasionally elongated ovoid pale nuclei and abundant eosinophilic cytoplasm (Figure 2A). Importantly, this feature was recognized by standard hematoxylin and eosin staining. It sometimes mimicked the morphological characteristics of collagenous colitis, although no apparent collagen band was identified (Figure 2B). In addition, this lesion is often confusing with the aggregation of vascular endothelium. We therefore performed immunohistochemical detection of CD31 and CD34, the well‐recognized makers of vascular endothelium. They were positive only in the interstitial blood vessels (Figure 2C). On the other hand, this feature was positive for CD68, indicating a monocyte/macrophage lineage (Figure 2D). Together with these morphological and immunohistochemical findings, these formations were identified as granuloma‐like lesions at the surface of the colon. We named this feature “subepithelial surface granulomatosis” (SSG), which is not found another type of colitis. Notably, these surface granulomas were located beneath the epithelium and often along the basal membrane, whereas small rounded granulomas are found deep in the colon in Crohn's disease. Cheese‐like necrosis, a typical histological feature of tuberculosis, was also not observed. While the UC‐like and GVHD‐like patterns were mutually exclusive, surface granuloma was found in both types of colitis. In addition, surface granuloma was observed even in a patient without significant symptoms or histological evidence of colitis other than granuloma (Case 9). Interestingly, eight of the nine patients with SSG achieved disease control (complete response, partial response, or stable disease). Moreover, eight of the 12 patients with disease control exhibited SSG in the colon tissue. However, likely because of the small sample size, this finding did not reach statistical significance (P = .13, Fisher's exact test).
FIGURE 2 Histopathological image of the subepithelial surface granulomatosis (SSG) found in the colon tissue after immune checkpoint inhibitor treatment. A, Representative histopathological image of SSG (arrows). Dotted lines indicate the epithelial‐subepithelial margin. Bar = 50 μm. B, SSG may sometimes mimic the collagenous band. Bar = 50 μm. C, SSG (arrows) may sometimes mimic the aggregation of vascular endothelium. SSG is negative for CD31 and CD34. Bar = 50 μm. D, SSG lesions diffusely express CD68, implying a histiocytic lineage (arrows). Bar = 50 μm
4 DISCUSSION
In this study, we investigated histopathological findings in irAE‐related colitis. The histological patterns of UC‐like and GVHD‐like pattern colitis have also been reported in some previous studies, although the differential mechanisms and clinicopathological importance of these patterns were unclear. 4 , 5 , 6 We identified SSG as a novel feature that was specific to colon tissue after ICI administration. PD‐1/programmed death‐ligand 1 (PD‐L1) inhibition sometimes complicates granuloma formation disorders, including sarcoid reaction and exacerbation of tuberculosis. 7 , 8 SSG formation appears to be a more frequent event than these granuloma‐forming adverse events. Granuloma formation after ICI administration can be attributed to a cellular immunity mechanism similar to that in mycobacterium tuberculosis infection. We assume that interferon‐gamma (IFNγ) is the key factor underlying the granuloma formation induced by ICIs (Figure 3). Indeed, IFNγ is an essential cytokine for granuloma formation in mycobacterium infection. 9 In addition, mycobacterium tuberculosis‐specific peripheral T lymphocytes release a large amount of IFNγ, which is used to diagnose tuberculosis infection. On the other hand, tumor antigen‐specific activated cytotoxic T lymphocytes (CTLs) produce abundant IFNγ, which leads to cancer cell death. Type 1 helper T cells would also be involved. The surface location of the SSG could be due to a reaction to enteric contents, including commensal bacteria, a potential determinant of clinical efficacy of ICIs. Consequently, SSG formation can be a hallmark of systemic CTL activation. Therefore, the histological finding of SSG may be useful as a surrogate marker for estimating the clinical effects of ICIs. Further clinicopathological investigation is required to determine the clinical significance of SSG in irAE histology.
FIGURE 3 Schematic diagram of the putative pathophysiology of granuloma formation as an immune‐related adverse event
Our study has some limitations. First, this study is based on a retrospective review of a limited number of medical records. The evaluation time points of the clinical response to the ICIs varied among patients. Grades of the intestinal symptoms were not available. In addition, multiple types of malignant tumors were included in the study. To obtain more reliable evidence, an appropriately designed prospective study is required, as well as a larger sample size and optimal control group. In addition, the appropriate biopsy timing or site should be identified. Second, even though SSG may a surrogate marker of systemic immune activation induced by ICIs, this marker might not necessarily reflect clinical efficacy. Immune activation may be a necessary but not sufficient condition. Although the immune system is activated, other immune escape mechanisms can inhibit cancer immunity. Third, only one patient who received a CTLA‐4 inhibitor was included in this study. CTLA‐4 inhibition may show a histology similar to that of autoimmune colitis in immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, a disease associated with regulatory T cell deficiency. 10 Further development of relevant biomarkers and their combination may provide a valid biomarker for estimating the clinical efficacy of ICIs.
In conclusion, we identified SSG as a characteristic histopathological feature of irAE‐associated enterocolitis. Because this was a pilot study with a small sample size, further investigation in a larger population is required, particularly in terms of the type of ICI, clinical efficacy for cancer, or other parameters. However, we believe that the results of this pilot study are valuable and indicate a promising direction of future research.
DISCLOSURE
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY-NC | 33459466 | 19,699,791 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Bilateral renal infarction in a patient with severe COVID-19 infection.
Thromboembolic events are frequent in patients with COVID-19 infection, and no cases of bilateral renal infarctions have been reported. We present the case of a 41-year-old female patient with diabetes mellitus and obesity who attended the emergency department for low back pain, respiratory failure associated with COVID-19 pneumonia, diabetic ketoacidosis, and shock. The patient had acute kidney injury and required hemodialysis. Contrast abdominal tomography showed bilateral renal infarction and anticoagulation was started. Kidney infarction cases require high diagnostic suspicion and possibility of starting anticoagulation.
Introduction
In December 2019, the novel coronavirus disease 2019 (COVID-19), a severe acute respiratory syndrome caused by the coronavirus 2 (SARS-CoV-2), was identified in China1. To date, there are more than 52 million infected people worldwide2 and although COVID-19 infection was initially described as a disease with respiratory symptoms, other clinical manifestations have been reported that make it a multisystemic disease3 - 5. Extrapulmonary manifestations include acute kidney injury6 , 7 and thromboembolic events8. Thromboembolic events in patients with COVID-19 are frequent and although the pathophysiologic mechanisms are not entirely clear, the most frequently referred thromboses are at the pulmonary and cerebral level9 , 10. The kidneys are organs susceptible to thrombosis, and evidence of thrombi at the level of glomerular capillaries has been found in necropsies of seriously ill patients11. Although to date some cases of patients with renal infarctions have been reported in patients with COVID-1912 - 14, these are unilateral, and to our knowledge, no case of bilateral renal infarction (BRI) has been reported. We report the case of a 41-year-old woman with severe COVID-19 infection and BRI.
Case report
A 41-year-old woman with obesity and 6 years of diabetes mellitus without treatment came to the emergency with a history of 7 days of fatigue and 2 days of dyspnea. Additionally, she reported bilateral and abdominal low back pain that partially improved with paracetamol.
At presentation, she was hemodynamically stable, had dyspnea, tachypnea, and an oxygen saturation of 80%. Chest radiography showed bilateral basal alveolar infiltrates and the rapid test was positive for IgM against COVID-19. Chest tomography found a bilateral ground glass pattern at the bottom that occupied 35% of the lung parenchyma without signs of pulmonary embolism.
Due to an initial glycemia of 500 mg/dL, urine ketones and severe metabolic acidosis, she was diagnosed with severe metabolic ketoacidosis. The main laboratory findings are shown in Table 1.
Table 1 Laboratory findings of the patient
Laboratory Findings* Patient Normal values
Hemoglobin, g/dL 6.9 13.7-17.7
Leukocytes, ×103/µL 21.8 4-10
Thrombocytes, ×103/µL 25.8 150-400
PO2, mm Hg 83 75-100
PcO2, mm Hg 44 35-45
pH 7.29 7.35-7.45
FiO % 0.4 0.21
Bicarbonate, mEq/L 20 21-25
Lactate, mg/dL 0.6 5.0-15
Glucose, mg/dL 158 80-100
CRP, mg/dL 210 < 0.5
Sodium, mEq/L 130 135-145
Potassium, mEq/L 5.7 3.5-5.5
Serum creatinine, mg/dL 5.73 0.6-1.2
Aspartate aminotransferase (U/L) 36 < 35
Alanine aminotransferase (U/L) 12 < 45
Coagulation
D-Dimer, ng/mL 1400 < 500
aPTT, s 30.6 25-36
PT, s 16.1 10-13
Fibrinogen, mg/dL 1036 200-400
Urinary Analysis **
Leukocyte 0 < 5/c
Erythrocytes 7 < /3
Proteins + -
Ketonic bodies +++ -
Immunologic Analyses
Antinuclear antibodies Negative
C3 (g/L) 1.46 0.88 - 2.01
C4 (g/L) 0.45 0.16 - 0.48
Anticardiolipin IgG (GPL/ml) Indeterminate < 17
Others
Serum homocysteine (µmol/L) 6.3 5-15
Protein C (%) 148 70–140
Protein S (%) 64 60–120
Antitrombin III (%) 124 80-120
* On the day of starting hemodialysis
** On the day of admission
CRP: C-reactive protein
aPTT: activated partial thromboplastin time
PT: prothrombin time
C3: Complement 3
C4: Complement 4
Initial management included oxygen therapy, hydration with saline, insulin, ceftriaxone, dexamethasone, and ivermectin. Three days later, low back and abdominal pain worsened, and a contrast abdominal tomography was requested, which showed perfusion defects in both kidneys, predominantly in the left kidney, suggestive of renal infarctions. (Figures 1 and 2). There was no evidence of extra renal thrombosis. Due to these findings, anticoagulation was started with enoxaparin 60 mg every 12 hours. Complementary physical examination showed no signs of peripheral ischemia and electrocardiogram showed sinus rhythm. She had no past history of atrial fibrillation.
Figure 1 Multiple perfusion defects in both kidneys, predominantly in left kidney.
Figure 2 Abdominal computed tomography showing thrombus in left kidney artery immediately before its bifurcation. The thrombus totally obstructs its previous division and partially obstructs the posterior division.
Respiratory and hemodynamic evolution of the patient was unfavorable, requiring mechanical ventilation and vasopressors. Subsequently, nine days later, the patient presented acute kidney injury (with oliguria, later anuria, and water overload) and conventional hemodialysis was started (the only type of hemodialysis available in our hospital) with non-tunneled catheter. Laboratory findings are shown in Table 1.
Two weeks later, the patient was still on hemodialysis, mechanical ventilation, and anticoagulation. She died in the third week of treatment.
Discussion
Renal infarction is relatively rare, as an emergency department study reported renal infarction in 0.004% of visits14. The main cause of renal infarction is cardioembolic event in patients with atrial fibrillation, but in half of cases there is no known cause15. Although low back pain, renal hypertension, and acute kidney injury have been described within its clinical manifestations, it can also present with nonspecific symptoms that make its diagnosis difficult15.
Nearly 20% of renal infarctions are bilateral15, and these have been reported in cases of dissecting aortic aneurysm, septic emboli in patients with endocarditis, lupus, vasculitis, sickle cell disease, fibromuscular dysplasia of renal arteries, secondary to non-steroidal anti-inflammatory drugs, and due to suspension of anticoagulation16 - 18. The clinical presentation of BRI is more dramatic than in cases of unilateral infarction, with cases of acute kidney injury being more frequent15 with clinical manifestations that may even be similar to rapidly progressive glomerulonephritis19. Although there are no significant difference in comorbidities, patients with BRI have a worse prognosis15.
Although acute kidney injury in patients with renal infarction is not uncommon, especially in patients with BRI, dialysis is required only in 11% of patients with unilateral infarction15. Thus, we could not affirm that our patient’s acute kidney injury was exclusively associated with renal infarction because it can be multifactorial20. The incidence of acute kidney injury in patients with severe COVID-19 infection varies between 19 to 36% and the dialysis requirement in these patients varies between 13 to 14%6 , 7. In our patient, factors such as effect of radiocontrast, shock, and dehydration from diabetic ketoacidosis are likely to have contributed to acute kidney injury.
Although not all tests were completed for the diagnosis of other causes of renal infarction, such as screening for sickle cell and genetic origin, these represent < 7% of causes15. Because of the described thromboembolic events in patients with COVID-19 infection, we hypothesized that this may be the most likely cause, which is supported by suggestive findings in necropsy of patients with severe COVID-19 infection11. Although the causes of this association are not entirely clear, it has been suggested that renal infarction may be associated with the direct cytopathic effect of the virus on endothelial cells, the presence of proinflammatory cytokines that stimulate the expression of tissue factors, or the formation of antiphospholipid antibodies21 , 22. Because the manifestations of a renal infarction could be subclinical, the diagnosis could be incidental and underestimated. Although there are no studies evaluating the effect of anticoagulation in patients with renal infarction, the possibility of the condition should be considered23.
In conclusion, we present the first case of BRI found incidentally in a patient with acute kidney injury and severe COVID-19 infection. The possibility of renal infarction in such cases should be considered given the need to start anticoagulation as a therapeutic measure. | CEFTRIAXONE, DEXAMETHASONE, ENOXAPARIN SODIUM, IVERMECTIN | DrugsGivenReaction | CC BY | 33460428 | 19,414,879 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Bilateral renal infarction in a patient with severe COVID-19 infection.
Thromboembolic events are frequent in patients with COVID-19 infection, and no cases of bilateral renal infarctions have been reported. We present the case of a 41-year-old female patient with diabetes mellitus and obesity who attended the emergency department for low back pain, respiratory failure associated with COVID-19 pneumonia, diabetic ketoacidosis, and shock. The patient had acute kidney injury and required hemodialysis. Contrast abdominal tomography showed bilateral renal infarction and anticoagulation was started. Kidney infarction cases require high diagnostic suspicion and possibility of starting anticoagulation.
Introduction
In December 2019, the novel coronavirus disease 2019 (COVID-19), a severe acute respiratory syndrome caused by the coronavirus 2 (SARS-CoV-2), was identified in China1. To date, there are more than 52 million infected people worldwide2 and although COVID-19 infection was initially described as a disease with respiratory symptoms, other clinical manifestations have been reported that make it a multisystemic disease3 - 5. Extrapulmonary manifestations include acute kidney injury6 , 7 and thromboembolic events8. Thromboembolic events in patients with COVID-19 are frequent and although the pathophysiologic mechanisms are not entirely clear, the most frequently referred thromboses are at the pulmonary and cerebral level9 , 10. The kidneys are organs susceptible to thrombosis, and evidence of thrombi at the level of glomerular capillaries has been found in necropsies of seriously ill patients11. Although to date some cases of patients with renal infarctions have been reported in patients with COVID-1912 - 14, these are unilateral, and to our knowledge, no case of bilateral renal infarction (BRI) has been reported. We report the case of a 41-year-old woman with severe COVID-19 infection and BRI.
Case report
A 41-year-old woman with obesity and 6 years of diabetes mellitus without treatment came to the emergency with a history of 7 days of fatigue and 2 days of dyspnea. Additionally, she reported bilateral and abdominal low back pain that partially improved with paracetamol.
At presentation, she was hemodynamically stable, had dyspnea, tachypnea, and an oxygen saturation of 80%. Chest radiography showed bilateral basal alveolar infiltrates and the rapid test was positive for IgM against COVID-19. Chest tomography found a bilateral ground glass pattern at the bottom that occupied 35% of the lung parenchyma without signs of pulmonary embolism.
Due to an initial glycemia of 500 mg/dL, urine ketones and severe metabolic acidosis, she was diagnosed with severe metabolic ketoacidosis. The main laboratory findings are shown in Table 1.
Table 1 Laboratory findings of the patient
Laboratory Findings* Patient Normal values
Hemoglobin, g/dL 6.9 13.7-17.7
Leukocytes, ×103/µL 21.8 4-10
Thrombocytes, ×103/µL 25.8 150-400
PO2, mm Hg 83 75-100
PcO2, mm Hg 44 35-45
pH 7.29 7.35-7.45
FiO % 0.4 0.21
Bicarbonate, mEq/L 20 21-25
Lactate, mg/dL 0.6 5.0-15
Glucose, mg/dL 158 80-100
CRP, mg/dL 210 < 0.5
Sodium, mEq/L 130 135-145
Potassium, mEq/L 5.7 3.5-5.5
Serum creatinine, mg/dL 5.73 0.6-1.2
Aspartate aminotransferase (U/L) 36 < 35
Alanine aminotransferase (U/L) 12 < 45
Coagulation
D-Dimer, ng/mL 1400 < 500
aPTT, s 30.6 25-36
PT, s 16.1 10-13
Fibrinogen, mg/dL 1036 200-400
Urinary Analysis **
Leukocyte 0 < 5/c
Erythrocytes 7 < /3
Proteins + -
Ketonic bodies +++ -
Immunologic Analyses
Antinuclear antibodies Negative
C3 (g/L) 1.46 0.88 - 2.01
C4 (g/L) 0.45 0.16 - 0.48
Anticardiolipin IgG (GPL/ml) Indeterminate < 17
Others
Serum homocysteine (µmol/L) 6.3 5-15
Protein C (%) 148 70–140
Protein S (%) 64 60–120
Antitrombin III (%) 124 80-120
* On the day of starting hemodialysis
** On the day of admission
CRP: C-reactive protein
aPTT: activated partial thromboplastin time
PT: prothrombin time
C3: Complement 3
C4: Complement 4
Initial management included oxygen therapy, hydration with saline, insulin, ceftriaxone, dexamethasone, and ivermectin. Three days later, low back and abdominal pain worsened, and a contrast abdominal tomography was requested, which showed perfusion defects in both kidneys, predominantly in the left kidney, suggestive of renal infarctions. (Figures 1 and 2). There was no evidence of extra renal thrombosis. Due to these findings, anticoagulation was started with enoxaparin 60 mg every 12 hours. Complementary physical examination showed no signs of peripheral ischemia and electrocardiogram showed sinus rhythm. She had no past history of atrial fibrillation.
Figure 1 Multiple perfusion defects in both kidneys, predominantly in left kidney.
Figure 2 Abdominal computed tomography showing thrombus in left kidney artery immediately before its bifurcation. The thrombus totally obstructs its previous division and partially obstructs the posterior division.
Respiratory and hemodynamic evolution of the patient was unfavorable, requiring mechanical ventilation and vasopressors. Subsequently, nine days later, the patient presented acute kidney injury (with oliguria, later anuria, and water overload) and conventional hemodialysis was started (the only type of hemodialysis available in our hospital) with non-tunneled catheter. Laboratory findings are shown in Table 1.
Two weeks later, the patient was still on hemodialysis, mechanical ventilation, and anticoagulation. She died in the third week of treatment.
Discussion
Renal infarction is relatively rare, as an emergency department study reported renal infarction in 0.004% of visits14. The main cause of renal infarction is cardioembolic event in patients with atrial fibrillation, but in half of cases there is no known cause15. Although low back pain, renal hypertension, and acute kidney injury have been described within its clinical manifestations, it can also present with nonspecific symptoms that make its diagnosis difficult15.
Nearly 20% of renal infarctions are bilateral15, and these have been reported in cases of dissecting aortic aneurysm, septic emboli in patients with endocarditis, lupus, vasculitis, sickle cell disease, fibromuscular dysplasia of renal arteries, secondary to non-steroidal anti-inflammatory drugs, and due to suspension of anticoagulation16 - 18. The clinical presentation of BRI is more dramatic than in cases of unilateral infarction, with cases of acute kidney injury being more frequent15 with clinical manifestations that may even be similar to rapidly progressive glomerulonephritis19. Although there are no significant difference in comorbidities, patients with BRI have a worse prognosis15.
Although acute kidney injury in patients with renal infarction is not uncommon, especially in patients with BRI, dialysis is required only in 11% of patients with unilateral infarction15. Thus, we could not affirm that our patient’s acute kidney injury was exclusively associated with renal infarction because it can be multifactorial20. The incidence of acute kidney injury in patients with severe COVID-19 infection varies between 19 to 36% and the dialysis requirement in these patients varies between 13 to 14%6 , 7. In our patient, factors such as effect of radiocontrast, shock, and dehydration from diabetic ketoacidosis are likely to have contributed to acute kidney injury.
Although not all tests were completed for the diagnosis of other causes of renal infarction, such as screening for sickle cell and genetic origin, these represent < 7% of causes15. Because of the described thromboembolic events in patients with COVID-19 infection, we hypothesized that this may be the most likely cause, which is supported by suggestive findings in necropsy of patients with severe COVID-19 infection11. Although the causes of this association are not entirely clear, it has been suggested that renal infarction may be associated with the direct cytopathic effect of the virus on endothelial cells, the presence of proinflammatory cytokines that stimulate the expression of tissue factors, or the formation of antiphospholipid antibodies21 , 22. Because the manifestations of a renal infarction could be subclinical, the diagnosis could be incidental and underestimated. Although there are no studies evaluating the effect of anticoagulation in patients with renal infarction, the possibility of the condition should be considered23.
In conclusion, we present the first case of BRI found incidentally in a patient with acute kidney injury and severe COVID-19 infection. The possibility of renal infarction in such cases should be considered given the need to start anticoagulation as a therapeutic measure. | CEFTRIAXONE, DEXAMETHASONE, ENOXAPARIN SODIUM, IVERMECTIN | DrugsGivenReaction | CC BY | 33460428 | 19,414,879 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Lessons Learned from a Fulminant Case of Reversible Cerebral Vasoconstriction Syndrome: Past Medical History Misleads the Diagnosis and Intra-Arterial Milrinone Offers Diagnostic Utility.
A 34-year-old post-partum female having dermatomyositis developed headache and became comatose after a seizure episode. Magnetic resonance imaging of brain showed a massive left ganglio-capsular bleed for which decompressive surgery was done. Computed tomographic angiography showed multiple foci of narrowing and irregularities in distal cerebral vessels. In view of dermatomyositis, the diagnosis of vasculitis was considered and pulse therapy of intravenous methylprednisolone was started. The patient, however, showed no improvement and developed new brain infarcts. She was subsequently taken up for a diagnostic cerebral angiography which showed multifocal severe narrowing in bilateral major cerebral arteries. These angiographic abnormalities showed excellent reversibility to intra-arterial milrinone and hence, reversible cerebral vasoconstriction syndrome (RCVS) was diagnosed. Normal angiographic findings in the first week do not rule out the disease and a repeat angiography should be considered if the clinical suspicion of the RCVS is high. Intra-arterial milrinone has a high diagnostic utility.
INTRODUCTION
The diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) often may be misleading and delayed because of the dynamic evolution of clinico-radiological features. RCVS is known to have an initial week of a hemorrhagic phase, which is later followed by ischemic complications. The angiographic features of RCVS are often best demonstrable only in the ischemic phase. Here, we present an unusual case of large basal ganglia hemorrhage in which the diagnosis was initially considered vasculitis. The diagnosis of RCVS was subsequently established by excellent angiographic reversibility to intra-arterial milrinone.
CASE REPORT
A 34-year-old pregnant female (gravida 4, para 2, abortion 1, intrauterine death 1) at 32 weeks of gestation presented with preterm premature rupture of membranes. The patient had a background history of dermatomyositis with interstitial lung disease in remission for the last 4 years. She was initially optimized on steroids and mycophenolate mofetil and subsequently switched to tacrolimus after detection of pregnancy. She underwent an uneventful emergency cesarean section under regional anesthesia. During the next day, she developed a moderately severe headache, which was holocranial and continuous. She had no features of raised intracranial tension. Her headache was not relieved with analgesics, and on the second postoperative day, she developed a generalized seizure during sleep. She continued to be in a comatose state following the seizure with a Glasgow Coma Scale score of eye opening (E)1, verbal response (V)2, best motor response (M)5. Serial blood pressure readings were normal in the post-partum period. Examination revealed bilateral pupils 1.5 mm in size and a sluggish reaction to light, along with a paucity of movements in the right extremities. Magnetic resonance imaging of the brain showed a large intra-parenchymal hematoma involving the left ganglio-capsular and frontotemporal regions causing a midline shift of 16 mm with intra-ventricular extension and uncal herniation (Fig. 1A). She underwent emergency craniotomy and hematoma evacuation. A postoperative computed tomography (CT) scan of the brain showed good evacuation of the hematoma and correction of midline shift (Fig. 1B). Computed tomography angiography (CTA) showed mild focal narrowing and irregularities in distal branches of bilateral middle cerebral arteries, anterior cerebral arteries, and posterior cerebral arteries (Fig. 1C). In the background of dermatomyositis and radiological findings, the possibility of vasculitis was considered. Erythrocyte sedimentation rate was 25 mm/h and C-reactive protein was 6 mg/L. Autoimmune workup for vasculitis including antinuclear antibody, antineutrophil cytoplasmic antibodies, rheumatoid factor, and antiphospholipid antibodies were negative. Viral serology for hepatitis B, hepatitis C, and human immunodeficiency virus was negative. Intravenous pulse methylprednisolone was given for 3 days; however, she continued to be in a deep coma. Serial follow-up CT scans of the brain did not show any hydrocephalus or bleed. Electroencephalogram did not show any epileptiform abnormalities. On the twelfth postoperative day, an examination revealed the patient to be in a quadriparetic state because of a newly developed left-sided weakness. A consequent CT brain showed multiple infarcts in the territories of the right anterior and middle cerebral arteries (Fig. 1D). Digital subtraction angiography (DSA) done on the same day showed severe narrowing and irregularity of bilateral anterior, middle, and posterior cerebral arteries, which showed excellent reversibility to intra-arterial milrinone infusion over 15 minutes (Fig. 1E, F). She was continued on intravenous milrinone infusion for 7 days. The diagnosis of RCVS was made secondary to her post-partum status, along with a possible etiological implication of tacrolimus therapy. Despite an RCVS2 score of only 4, which implies a low diagnostic sensitivity for the syndrome, the diagnosis of RCVS as opposed to vasculitis, was supported by excellent reversibility of angiographic abnormalities to milrinone [1]. Subsequently, the patient gradually recovered from her comatose state and started moving her right upper and lower limbs. CTA done before the discharge from the hospital in the sixth postoperative week showed no significant abnormalities. She was conscious and alert at the time of discharge with a power of grade 3/5 and 2/5 in her right and left extremities, respectively. Her neurological recovery is expected to be delayed due to bihemispheric dysfunction and multiple infarcts in the right cerebral hemisphere before milrinone therapy.
DISCUSSION
RCVS is a clinical and radiological syndrome characterized by sudden severe headache and reversible multifocal narrowing of cerebral arteries [2]. This syndrome is often considered to have a benign outcome; however, major strokes resulting in severe disability and death have been reported [3]. A recent systematic review has observed intracerebral hemorrhage (ICH) as the most common presentation (42%) in fatal RCVS cases, followed by encephalopathy and/or headaches in 25%, and ischemic stroke and posterior reversible encephalopathy syndrome in 16.5% each [4]. The same review noted that half of these fatal cases initially presented with a non-specific headache (NSH). Our patient also had NSH as the initial manifestation. Diagnosis of RCVS can often be delayed due to the dynamic natural history and radiological features of the disease. Stroke may occur after a few days of the initial normal brain imaging. Further, angiographic vasoconstriction may show up the best only after 2–3 weeks of the clinical onset [3].
In the present case, we were deceived initially by the mild distal focal narrowings on CTA, which steered our diagnosis towards cerebral vasculitis especially against the backdrop of dermatomyositis. Central nervous system vasculitis is known to be associated with ICH [5]. Consequently, we started pulse therapy of intravenous methylprednisolone; the patient, however, continued to be in a comatose state. She instead developed new cerebral infarcts, and hence underwent DSA, which revealed severe multi-focal narrowings that demonstrated a striking reversal on the administration of intra-arterial milrinone. So, a probable diagnosis of RCVS was established, which was further supported by the normal CTA in the sixth postoperative week. In the retrospect, however, we understand that corticosteroid use may result in a poor outcome in RCVS and should be avoided, although, in our case, it was used considering the possibility of vasculitis before the diagnosis got confirmed [6,7].
This case of fulminant RCVS was unusual and left us with several learning lessons. First, the diagnosis was delayed because of the characteristically dynamic natural history of the disease. Clinically, our patient presented with a non-specific headache initially, as against a thunderclap headache which is classically seen in RCVS. Furthermore, this disease is described as having an initial hemorrhagic phase followed by an ischemic phase in the second week [8-10]. It is also characterized by minimal angiographic findings in the initial hemorrhagic phase when the vasospasm is in the distal vessels, which is followed by proximal migration of vasospasm causing ischemic strokes in the second phase [8]. Although the evolution of radiological changes with time has been described in the literature, this case highlights how this may cause confusion in the diagnosis and require caution in evaluating such cases. Normal angiography in the first week may not rule out the disease and a repeat angiography may be warranted if the clinical suspicion of the RCVS is high. Further, our patient had a massive ganglio-capsular regional bleed, which has rarely been mentioned in the medical literature. RCVS commonly presents in the hemorrhagic phase as SAH and cortical bleeds [3]. It may be noted that the presence of a large basal ganglia hemorrhage should not preclude one from considering RCVS as a diagnosis, especially in an appropriate clinical setting such as a post-partum state. The exposure of our patient to tacrolimus further strengthened the associated risk.
Lastly, the high diagnostic utility of intra-arterial milrinone for RCVS has a mere anecdotal mention in the literature [11]. We, however, observed it to have a dramatic role in reversing the vasoconstriction; and thus, it has a remarkable potential for differentiating RCVS from vasculitis. In the medical literature though, angiographic response to intra-arterial vasodilators is varied and there is a lack of strong evidence for the therapeutic role of the same in RCVS [11-14]. Randomized studies conducted on the role of Nimodipine for the same have not shown any significant benefit [15,16]. Thus, our case may be considered as a potential source for conducting further randomized studies in this regard. It would be worthwhile to see if the diagnostic utility of milrinone as observed in our case can be established further with well-designed prospective studies. In conclusion, intra-arterial milrinone appears to have a significant diagnostic utility for RCVS.
Fig. 1. (A) Magnetic resonance imaging of brain showing large intra-parenchymal hematoma involving left ganglio-capsular and frontotemporal regions with significant midline shift. (B) Post-operative computed tomography (CT) scan of brain showing hematoma evacuation. (C) CT angiography demonstrating multifocal luminal irregularities and narrowing (white arrowheads) of distal branches of bilateral middle and posterior cerebral arteries. (D) CT brain on twelfth postoperative day showing multiple acute infarcts (white arrows) in right middle cerebral arteries (MCA) territory. (E) Digital subtraction angiography performed in the second week showing severe proximal narrowing of left MCA (black thick arrow) and the anterior cerebral arteries (ACA) (black thin arrow). (F) Post intra-arterial milrinone injection of left internal carotid artery showing excellent reversibility of MCA and ACA abnormalities.
Fund
None.
Ethics Statement
This study was a case report, ethical approval was not required; however, informed consent was taken from the patient’s close relatives for presenting the patient’s data as a report.
Conflicts of Interest
The authors have no conflicts to disclose.
Author Contribution
Concept and design: PJA, AP, GVK, and KS. Analysis and interpretation: PJA, AP, and GVK. Data collection: PJA and AP. Writing the article: PJA, AP, and KS. Critical revision of the article: PJA, AP, GVK, and KS. Final approval of the article: PJA, AP, GVK, and KS. Overall responsibility: AP. | TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33460536 | 19,025,099 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Reversible cerebral vasoconstriction syndrome'. | Lessons Learned from a Fulminant Case of Reversible Cerebral Vasoconstriction Syndrome: Past Medical History Misleads the Diagnosis and Intra-Arterial Milrinone Offers Diagnostic Utility.
A 34-year-old post-partum female having dermatomyositis developed headache and became comatose after a seizure episode. Magnetic resonance imaging of brain showed a massive left ganglio-capsular bleed for which decompressive surgery was done. Computed tomographic angiography showed multiple foci of narrowing and irregularities in distal cerebral vessels. In view of dermatomyositis, the diagnosis of vasculitis was considered and pulse therapy of intravenous methylprednisolone was started. The patient, however, showed no improvement and developed new brain infarcts. She was subsequently taken up for a diagnostic cerebral angiography which showed multifocal severe narrowing in bilateral major cerebral arteries. These angiographic abnormalities showed excellent reversibility to intra-arterial milrinone and hence, reversible cerebral vasoconstriction syndrome (RCVS) was diagnosed. Normal angiographic findings in the first week do not rule out the disease and a repeat angiography should be considered if the clinical suspicion of the RCVS is high. Intra-arterial milrinone has a high diagnostic utility.
INTRODUCTION
The diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) often may be misleading and delayed because of the dynamic evolution of clinico-radiological features. RCVS is known to have an initial week of a hemorrhagic phase, which is later followed by ischemic complications. The angiographic features of RCVS are often best demonstrable only in the ischemic phase. Here, we present an unusual case of large basal ganglia hemorrhage in which the diagnosis was initially considered vasculitis. The diagnosis of RCVS was subsequently established by excellent angiographic reversibility to intra-arterial milrinone.
CASE REPORT
A 34-year-old pregnant female (gravida 4, para 2, abortion 1, intrauterine death 1) at 32 weeks of gestation presented with preterm premature rupture of membranes. The patient had a background history of dermatomyositis with interstitial lung disease in remission for the last 4 years. She was initially optimized on steroids and mycophenolate mofetil and subsequently switched to tacrolimus after detection of pregnancy. She underwent an uneventful emergency cesarean section under regional anesthesia. During the next day, she developed a moderately severe headache, which was holocranial and continuous. She had no features of raised intracranial tension. Her headache was not relieved with analgesics, and on the second postoperative day, she developed a generalized seizure during sleep. She continued to be in a comatose state following the seizure with a Glasgow Coma Scale score of eye opening (E)1, verbal response (V)2, best motor response (M)5. Serial blood pressure readings were normal in the post-partum period. Examination revealed bilateral pupils 1.5 mm in size and a sluggish reaction to light, along with a paucity of movements in the right extremities. Magnetic resonance imaging of the brain showed a large intra-parenchymal hematoma involving the left ganglio-capsular and frontotemporal regions causing a midline shift of 16 mm with intra-ventricular extension and uncal herniation (Fig. 1A). She underwent emergency craniotomy and hematoma evacuation. A postoperative computed tomography (CT) scan of the brain showed good evacuation of the hematoma and correction of midline shift (Fig. 1B). Computed tomography angiography (CTA) showed mild focal narrowing and irregularities in distal branches of bilateral middle cerebral arteries, anterior cerebral arteries, and posterior cerebral arteries (Fig. 1C). In the background of dermatomyositis and radiological findings, the possibility of vasculitis was considered. Erythrocyte sedimentation rate was 25 mm/h and C-reactive protein was 6 mg/L. Autoimmune workup for vasculitis including antinuclear antibody, antineutrophil cytoplasmic antibodies, rheumatoid factor, and antiphospholipid antibodies were negative. Viral serology for hepatitis B, hepatitis C, and human immunodeficiency virus was negative. Intravenous pulse methylprednisolone was given for 3 days; however, she continued to be in a deep coma. Serial follow-up CT scans of the brain did not show any hydrocephalus or bleed. Electroencephalogram did not show any epileptiform abnormalities. On the twelfth postoperative day, an examination revealed the patient to be in a quadriparetic state because of a newly developed left-sided weakness. A consequent CT brain showed multiple infarcts in the territories of the right anterior and middle cerebral arteries (Fig. 1D). Digital subtraction angiography (DSA) done on the same day showed severe narrowing and irregularity of bilateral anterior, middle, and posterior cerebral arteries, which showed excellent reversibility to intra-arterial milrinone infusion over 15 minutes (Fig. 1E, F). She was continued on intravenous milrinone infusion for 7 days. The diagnosis of RCVS was made secondary to her post-partum status, along with a possible etiological implication of tacrolimus therapy. Despite an RCVS2 score of only 4, which implies a low diagnostic sensitivity for the syndrome, the diagnosis of RCVS as opposed to vasculitis, was supported by excellent reversibility of angiographic abnormalities to milrinone [1]. Subsequently, the patient gradually recovered from her comatose state and started moving her right upper and lower limbs. CTA done before the discharge from the hospital in the sixth postoperative week showed no significant abnormalities. She was conscious and alert at the time of discharge with a power of grade 3/5 and 2/5 in her right and left extremities, respectively. Her neurological recovery is expected to be delayed due to bihemispheric dysfunction and multiple infarcts in the right cerebral hemisphere before milrinone therapy.
DISCUSSION
RCVS is a clinical and radiological syndrome characterized by sudden severe headache and reversible multifocal narrowing of cerebral arteries [2]. This syndrome is often considered to have a benign outcome; however, major strokes resulting in severe disability and death have been reported [3]. A recent systematic review has observed intracerebral hemorrhage (ICH) as the most common presentation (42%) in fatal RCVS cases, followed by encephalopathy and/or headaches in 25%, and ischemic stroke and posterior reversible encephalopathy syndrome in 16.5% each [4]. The same review noted that half of these fatal cases initially presented with a non-specific headache (NSH). Our patient also had NSH as the initial manifestation. Diagnosis of RCVS can often be delayed due to the dynamic natural history and radiological features of the disease. Stroke may occur after a few days of the initial normal brain imaging. Further, angiographic vasoconstriction may show up the best only after 2–3 weeks of the clinical onset [3].
In the present case, we were deceived initially by the mild distal focal narrowings on CTA, which steered our diagnosis towards cerebral vasculitis especially against the backdrop of dermatomyositis. Central nervous system vasculitis is known to be associated with ICH [5]. Consequently, we started pulse therapy of intravenous methylprednisolone; the patient, however, continued to be in a comatose state. She instead developed new cerebral infarcts, and hence underwent DSA, which revealed severe multi-focal narrowings that demonstrated a striking reversal on the administration of intra-arterial milrinone. So, a probable diagnosis of RCVS was established, which was further supported by the normal CTA in the sixth postoperative week. In the retrospect, however, we understand that corticosteroid use may result in a poor outcome in RCVS and should be avoided, although, in our case, it was used considering the possibility of vasculitis before the diagnosis got confirmed [6,7].
This case of fulminant RCVS was unusual and left us with several learning lessons. First, the diagnosis was delayed because of the characteristically dynamic natural history of the disease. Clinically, our patient presented with a non-specific headache initially, as against a thunderclap headache which is classically seen in RCVS. Furthermore, this disease is described as having an initial hemorrhagic phase followed by an ischemic phase in the second week [8-10]. It is also characterized by minimal angiographic findings in the initial hemorrhagic phase when the vasospasm is in the distal vessels, which is followed by proximal migration of vasospasm causing ischemic strokes in the second phase [8]. Although the evolution of radiological changes with time has been described in the literature, this case highlights how this may cause confusion in the diagnosis and require caution in evaluating such cases. Normal angiography in the first week may not rule out the disease and a repeat angiography may be warranted if the clinical suspicion of the RCVS is high. Further, our patient had a massive ganglio-capsular regional bleed, which has rarely been mentioned in the medical literature. RCVS commonly presents in the hemorrhagic phase as SAH and cortical bleeds [3]. It may be noted that the presence of a large basal ganglia hemorrhage should not preclude one from considering RCVS as a diagnosis, especially in an appropriate clinical setting such as a post-partum state. The exposure of our patient to tacrolimus further strengthened the associated risk.
Lastly, the high diagnostic utility of intra-arterial milrinone for RCVS has a mere anecdotal mention in the literature [11]. We, however, observed it to have a dramatic role in reversing the vasoconstriction; and thus, it has a remarkable potential for differentiating RCVS from vasculitis. In the medical literature though, angiographic response to intra-arterial vasodilators is varied and there is a lack of strong evidence for the therapeutic role of the same in RCVS [11-14]. Randomized studies conducted on the role of Nimodipine for the same have not shown any significant benefit [15,16]. Thus, our case may be considered as a potential source for conducting further randomized studies in this regard. It would be worthwhile to see if the diagnostic utility of milrinone as observed in our case can be established further with well-designed prospective studies. In conclusion, intra-arterial milrinone appears to have a significant diagnostic utility for RCVS.
Fig. 1. (A) Magnetic resonance imaging of brain showing large intra-parenchymal hematoma involving left ganglio-capsular and frontotemporal regions with significant midline shift. (B) Post-operative computed tomography (CT) scan of brain showing hematoma evacuation. (C) CT angiography demonstrating multifocal luminal irregularities and narrowing (white arrowheads) of distal branches of bilateral middle and posterior cerebral arteries. (D) CT brain on twelfth postoperative day showing multiple acute infarcts (white arrows) in right middle cerebral arteries (MCA) territory. (E) Digital subtraction angiography performed in the second week showing severe proximal narrowing of left MCA (black thick arrow) and the anterior cerebral arteries (ACA) (black thin arrow). (F) Post intra-arterial milrinone injection of left internal carotid artery showing excellent reversibility of MCA and ACA abnormalities.
Fund
None.
Ethics Statement
This study was a case report, ethical approval was not required; however, informed consent was taken from the patient’s close relatives for presenting the patient’s data as a report.
Conflicts of Interest
The authors have no conflicts to disclose.
Author Contribution
Concept and design: PJA, AP, GVK, and KS. Analysis and interpretation: PJA, AP, and GVK. Data collection: PJA and AP. Writing the article: PJA, AP, and KS. Critical revision of the article: PJA, AP, GVK, and KS. Final approval of the article: PJA, AP, GVK, and KS. Overall responsibility: AP. | TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33460536 | 19,025,099 | 2021-03 |
What was the dosage of drug 'TACROLIMUS'? | Lessons Learned from a Fulminant Case of Reversible Cerebral Vasoconstriction Syndrome: Past Medical History Misleads the Diagnosis and Intra-Arterial Milrinone Offers Diagnostic Utility.
A 34-year-old post-partum female having dermatomyositis developed headache and became comatose after a seizure episode. Magnetic resonance imaging of brain showed a massive left ganglio-capsular bleed for which decompressive surgery was done. Computed tomographic angiography showed multiple foci of narrowing and irregularities in distal cerebral vessels. In view of dermatomyositis, the diagnosis of vasculitis was considered and pulse therapy of intravenous methylprednisolone was started. The patient, however, showed no improvement and developed new brain infarcts. She was subsequently taken up for a diagnostic cerebral angiography which showed multifocal severe narrowing in bilateral major cerebral arteries. These angiographic abnormalities showed excellent reversibility to intra-arterial milrinone and hence, reversible cerebral vasoconstriction syndrome (RCVS) was diagnosed. Normal angiographic findings in the first week do not rule out the disease and a repeat angiography should be considered if the clinical suspicion of the RCVS is high. Intra-arterial milrinone has a high diagnostic utility.
INTRODUCTION
The diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) often may be misleading and delayed because of the dynamic evolution of clinico-radiological features. RCVS is known to have an initial week of a hemorrhagic phase, which is later followed by ischemic complications. The angiographic features of RCVS are often best demonstrable only in the ischemic phase. Here, we present an unusual case of large basal ganglia hemorrhage in which the diagnosis was initially considered vasculitis. The diagnosis of RCVS was subsequently established by excellent angiographic reversibility to intra-arterial milrinone.
CASE REPORT
A 34-year-old pregnant female (gravida 4, para 2, abortion 1, intrauterine death 1) at 32 weeks of gestation presented with preterm premature rupture of membranes. The patient had a background history of dermatomyositis with interstitial lung disease in remission for the last 4 years. She was initially optimized on steroids and mycophenolate mofetil and subsequently switched to tacrolimus after detection of pregnancy. She underwent an uneventful emergency cesarean section under regional anesthesia. During the next day, she developed a moderately severe headache, which was holocranial and continuous. She had no features of raised intracranial tension. Her headache was not relieved with analgesics, and on the second postoperative day, she developed a generalized seizure during sleep. She continued to be in a comatose state following the seizure with a Glasgow Coma Scale score of eye opening (E)1, verbal response (V)2, best motor response (M)5. Serial blood pressure readings were normal in the post-partum period. Examination revealed bilateral pupils 1.5 mm in size and a sluggish reaction to light, along with a paucity of movements in the right extremities. Magnetic resonance imaging of the brain showed a large intra-parenchymal hematoma involving the left ganglio-capsular and frontotemporal regions causing a midline shift of 16 mm with intra-ventricular extension and uncal herniation (Fig. 1A). She underwent emergency craniotomy and hematoma evacuation. A postoperative computed tomography (CT) scan of the brain showed good evacuation of the hematoma and correction of midline shift (Fig. 1B). Computed tomography angiography (CTA) showed mild focal narrowing and irregularities in distal branches of bilateral middle cerebral arteries, anterior cerebral arteries, and posterior cerebral arteries (Fig. 1C). In the background of dermatomyositis and radiological findings, the possibility of vasculitis was considered. Erythrocyte sedimentation rate was 25 mm/h and C-reactive protein was 6 mg/L. Autoimmune workup for vasculitis including antinuclear antibody, antineutrophil cytoplasmic antibodies, rheumatoid factor, and antiphospholipid antibodies were negative. Viral serology for hepatitis B, hepatitis C, and human immunodeficiency virus was negative. Intravenous pulse methylprednisolone was given for 3 days; however, she continued to be in a deep coma. Serial follow-up CT scans of the brain did not show any hydrocephalus or bleed. Electroencephalogram did not show any epileptiform abnormalities. On the twelfth postoperative day, an examination revealed the patient to be in a quadriparetic state because of a newly developed left-sided weakness. A consequent CT brain showed multiple infarcts in the territories of the right anterior and middle cerebral arteries (Fig. 1D). Digital subtraction angiography (DSA) done on the same day showed severe narrowing and irregularity of bilateral anterior, middle, and posterior cerebral arteries, which showed excellent reversibility to intra-arterial milrinone infusion over 15 minutes (Fig. 1E, F). She was continued on intravenous milrinone infusion for 7 days. The diagnosis of RCVS was made secondary to her post-partum status, along with a possible etiological implication of tacrolimus therapy. Despite an RCVS2 score of only 4, which implies a low diagnostic sensitivity for the syndrome, the diagnosis of RCVS as opposed to vasculitis, was supported by excellent reversibility of angiographic abnormalities to milrinone [1]. Subsequently, the patient gradually recovered from her comatose state and started moving her right upper and lower limbs. CTA done before the discharge from the hospital in the sixth postoperative week showed no significant abnormalities. She was conscious and alert at the time of discharge with a power of grade 3/5 and 2/5 in her right and left extremities, respectively. Her neurological recovery is expected to be delayed due to bihemispheric dysfunction and multiple infarcts in the right cerebral hemisphere before milrinone therapy.
DISCUSSION
RCVS is a clinical and radiological syndrome characterized by sudden severe headache and reversible multifocal narrowing of cerebral arteries [2]. This syndrome is often considered to have a benign outcome; however, major strokes resulting in severe disability and death have been reported [3]. A recent systematic review has observed intracerebral hemorrhage (ICH) as the most common presentation (42%) in fatal RCVS cases, followed by encephalopathy and/or headaches in 25%, and ischemic stroke and posterior reversible encephalopathy syndrome in 16.5% each [4]. The same review noted that half of these fatal cases initially presented with a non-specific headache (NSH). Our patient also had NSH as the initial manifestation. Diagnosis of RCVS can often be delayed due to the dynamic natural history and radiological features of the disease. Stroke may occur after a few days of the initial normal brain imaging. Further, angiographic vasoconstriction may show up the best only after 2–3 weeks of the clinical onset [3].
In the present case, we were deceived initially by the mild distal focal narrowings on CTA, which steered our diagnosis towards cerebral vasculitis especially against the backdrop of dermatomyositis. Central nervous system vasculitis is known to be associated with ICH [5]. Consequently, we started pulse therapy of intravenous methylprednisolone; the patient, however, continued to be in a comatose state. She instead developed new cerebral infarcts, and hence underwent DSA, which revealed severe multi-focal narrowings that demonstrated a striking reversal on the administration of intra-arterial milrinone. So, a probable diagnosis of RCVS was established, which was further supported by the normal CTA in the sixth postoperative week. In the retrospect, however, we understand that corticosteroid use may result in a poor outcome in RCVS and should be avoided, although, in our case, it was used considering the possibility of vasculitis before the diagnosis got confirmed [6,7].
This case of fulminant RCVS was unusual and left us with several learning lessons. First, the diagnosis was delayed because of the characteristically dynamic natural history of the disease. Clinically, our patient presented with a non-specific headache initially, as against a thunderclap headache which is classically seen in RCVS. Furthermore, this disease is described as having an initial hemorrhagic phase followed by an ischemic phase in the second week [8-10]. It is also characterized by minimal angiographic findings in the initial hemorrhagic phase when the vasospasm is in the distal vessels, which is followed by proximal migration of vasospasm causing ischemic strokes in the second phase [8]. Although the evolution of radiological changes with time has been described in the literature, this case highlights how this may cause confusion in the diagnosis and require caution in evaluating such cases. Normal angiography in the first week may not rule out the disease and a repeat angiography may be warranted if the clinical suspicion of the RCVS is high. Further, our patient had a massive ganglio-capsular regional bleed, which has rarely been mentioned in the medical literature. RCVS commonly presents in the hemorrhagic phase as SAH and cortical bleeds [3]. It may be noted that the presence of a large basal ganglia hemorrhage should not preclude one from considering RCVS as a diagnosis, especially in an appropriate clinical setting such as a post-partum state. The exposure of our patient to tacrolimus further strengthened the associated risk.
Lastly, the high diagnostic utility of intra-arterial milrinone for RCVS has a mere anecdotal mention in the literature [11]. We, however, observed it to have a dramatic role in reversing the vasoconstriction; and thus, it has a remarkable potential for differentiating RCVS from vasculitis. In the medical literature though, angiographic response to intra-arterial vasodilators is varied and there is a lack of strong evidence for the therapeutic role of the same in RCVS [11-14]. Randomized studies conducted on the role of Nimodipine for the same have not shown any significant benefit [15,16]. Thus, our case may be considered as a potential source for conducting further randomized studies in this regard. It would be worthwhile to see if the diagnostic utility of milrinone as observed in our case can be established further with well-designed prospective studies. In conclusion, intra-arterial milrinone appears to have a significant diagnostic utility for RCVS.
Fig. 1. (A) Magnetic resonance imaging of brain showing large intra-parenchymal hematoma involving left ganglio-capsular and frontotemporal regions with significant midline shift. (B) Post-operative computed tomography (CT) scan of brain showing hematoma evacuation. (C) CT angiography demonstrating multifocal luminal irregularities and narrowing (white arrowheads) of distal branches of bilateral middle and posterior cerebral arteries. (D) CT brain on twelfth postoperative day showing multiple acute infarcts (white arrows) in right middle cerebral arteries (MCA) territory. (E) Digital subtraction angiography performed in the second week showing severe proximal narrowing of left MCA (black thick arrow) and the anterior cerebral arteries (ACA) (black thin arrow). (F) Post intra-arterial milrinone injection of left internal carotid artery showing excellent reversibility of MCA and ACA abnormalities.
Fund
None.
Ethics Statement
This study was a case report, ethical approval was not required; however, informed consent was taken from the patient’s close relatives for presenting the patient’s data as a report.
Conflicts of Interest
The authors have no conflicts to disclose.
Author Contribution
Concept and design: PJA, AP, GVK, and KS. Analysis and interpretation: PJA, AP, and GVK. Data collection: PJA and AP. Writing the article: PJA, AP, and KS. Critical revision of the article: PJA, AP, GVK, and KS. Final approval of the article: PJA, AP, GVK, and KS. Overall responsibility: AP. | UNK UNK, UNKNOWN FREQ. | DrugDosageText | CC BY-NC | 33460536 | 19,025,099 | 2021-03 |
What was the outcome of reaction 'Reversible cerebral vasoconstriction syndrome'? | Lessons Learned from a Fulminant Case of Reversible Cerebral Vasoconstriction Syndrome: Past Medical History Misleads the Diagnosis and Intra-Arterial Milrinone Offers Diagnostic Utility.
A 34-year-old post-partum female having dermatomyositis developed headache and became comatose after a seizure episode. Magnetic resonance imaging of brain showed a massive left ganglio-capsular bleed for which decompressive surgery was done. Computed tomographic angiography showed multiple foci of narrowing and irregularities in distal cerebral vessels. In view of dermatomyositis, the diagnosis of vasculitis was considered and pulse therapy of intravenous methylprednisolone was started. The patient, however, showed no improvement and developed new brain infarcts. She was subsequently taken up for a diagnostic cerebral angiography which showed multifocal severe narrowing in bilateral major cerebral arteries. These angiographic abnormalities showed excellent reversibility to intra-arterial milrinone and hence, reversible cerebral vasoconstriction syndrome (RCVS) was diagnosed. Normal angiographic findings in the first week do not rule out the disease and a repeat angiography should be considered if the clinical suspicion of the RCVS is high. Intra-arterial milrinone has a high diagnostic utility.
INTRODUCTION
The diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) often may be misleading and delayed because of the dynamic evolution of clinico-radiological features. RCVS is known to have an initial week of a hemorrhagic phase, which is later followed by ischemic complications. The angiographic features of RCVS are often best demonstrable only in the ischemic phase. Here, we present an unusual case of large basal ganglia hemorrhage in which the diagnosis was initially considered vasculitis. The diagnosis of RCVS was subsequently established by excellent angiographic reversibility to intra-arterial milrinone.
CASE REPORT
A 34-year-old pregnant female (gravida 4, para 2, abortion 1, intrauterine death 1) at 32 weeks of gestation presented with preterm premature rupture of membranes. The patient had a background history of dermatomyositis with interstitial lung disease in remission for the last 4 years. She was initially optimized on steroids and mycophenolate mofetil and subsequently switched to tacrolimus after detection of pregnancy. She underwent an uneventful emergency cesarean section under regional anesthesia. During the next day, she developed a moderately severe headache, which was holocranial and continuous. She had no features of raised intracranial tension. Her headache was not relieved with analgesics, and on the second postoperative day, she developed a generalized seizure during sleep. She continued to be in a comatose state following the seizure with a Glasgow Coma Scale score of eye opening (E)1, verbal response (V)2, best motor response (M)5. Serial blood pressure readings were normal in the post-partum period. Examination revealed bilateral pupils 1.5 mm in size and a sluggish reaction to light, along with a paucity of movements in the right extremities. Magnetic resonance imaging of the brain showed a large intra-parenchymal hematoma involving the left ganglio-capsular and frontotemporal regions causing a midline shift of 16 mm with intra-ventricular extension and uncal herniation (Fig. 1A). She underwent emergency craniotomy and hematoma evacuation. A postoperative computed tomography (CT) scan of the brain showed good evacuation of the hematoma and correction of midline shift (Fig. 1B). Computed tomography angiography (CTA) showed mild focal narrowing and irregularities in distal branches of bilateral middle cerebral arteries, anterior cerebral arteries, and posterior cerebral arteries (Fig. 1C). In the background of dermatomyositis and radiological findings, the possibility of vasculitis was considered. Erythrocyte sedimentation rate was 25 mm/h and C-reactive protein was 6 mg/L. Autoimmune workup for vasculitis including antinuclear antibody, antineutrophil cytoplasmic antibodies, rheumatoid factor, and antiphospholipid antibodies were negative. Viral serology for hepatitis B, hepatitis C, and human immunodeficiency virus was negative. Intravenous pulse methylprednisolone was given for 3 days; however, she continued to be in a deep coma. Serial follow-up CT scans of the brain did not show any hydrocephalus or bleed. Electroencephalogram did not show any epileptiform abnormalities. On the twelfth postoperative day, an examination revealed the patient to be in a quadriparetic state because of a newly developed left-sided weakness. A consequent CT brain showed multiple infarcts in the territories of the right anterior and middle cerebral arteries (Fig. 1D). Digital subtraction angiography (DSA) done on the same day showed severe narrowing and irregularity of bilateral anterior, middle, and posterior cerebral arteries, which showed excellent reversibility to intra-arterial milrinone infusion over 15 minutes (Fig. 1E, F). She was continued on intravenous milrinone infusion for 7 days. The diagnosis of RCVS was made secondary to her post-partum status, along with a possible etiological implication of tacrolimus therapy. Despite an RCVS2 score of only 4, which implies a low diagnostic sensitivity for the syndrome, the diagnosis of RCVS as opposed to vasculitis, was supported by excellent reversibility of angiographic abnormalities to milrinone [1]. Subsequently, the patient gradually recovered from her comatose state and started moving her right upper and lower limbs. CTA done before the discharge from the hospital in the sixth postoperative week showed no significant abnormalities. She was conscious and alert at the time of discharge with a power of grade 3/5 and 2/5 in her right and left extremities, respectively. Her neurological recovery is expected to be delayed due to bihemispheric dysfunction and multiple infarcts in the right cerebral hemisphere before milrinone therapy.
DISCUSSION
RCVS is a clinical and radiological syndrome characterized by sudden severe headache and reversible multifocal narrowing of cerebral arteries [2]. This syndrome is often considered to have a benign outcome; however, major strokes resulting in severe disability and death have been reported [3]. A recent systematic review has observed intracerebral hemorrhage (ICH) as the most common presentation (42%) in fatal RCVS cases, followed by encephalopathy and/or headaches in 25%, and ischemic stroke and posterior reversible encephalopathy syndrome in 16.5% each [4]. The same review noted that half of these fatal cases initially presented with a non-specific headache (NSH). Our patient also had NSH as the initial manifestation. Diagnosis of RCVS can often be delayed due to the dynamic natural history and radiological features of the disease. Stroke may occur after a few days of the initial normal brain imaging. Further, angiographic vasoconstriction may show up the best only after 2–3 weeks of the clinical onset [3].
In the present case, we were deceived initially by the mild distal focal narrowings on CTA, which steered our diagnosis towards cerebral vasculitis especially against the backdrop of dermatomyositis. Central nervous system vasculitis is known to be associated with ICH [5]. Consequently, we started pulse therapy of intravenous methylprednisolone; the patient, however, continued to be in a comatose state. She instead developed new cerebral infarcts, and hence underwent DSA, which revealed severe multi-focal narrowings that demonstrated a striking reversal on the administration of intra-arterial milrinone. So, a probable diagnosis of RCVS was established, which was further supported by the normal CTA in the sixth postoperative week. In the retrospect, however, we understand that corticosteroid use may result in a poor outcome in RCVS and should be avoided, although, in our case, it was used considering the possibility of vasculitis before the diagnosis got confirmed [6,7].
This case of fulminant RCVS was unusual and left us with several learning lessons. First, the diagnosis was delayed because of the characteristically dynamic natural history of the disease. Clinically, our patient presented with a non-specific headache initially, as against a thunderclap headache which is classically seen in RCVS. Furthermore, this disease is described as having an initial hemorrhagic phase followed by an ischemic phase in the second week [8-10]. It is also characterized by minimal angiographic findings in the initial hemorrhagic phase when the vasospasm is in the distal vessels, which is followed by proximal migration of vasospasm causing ischemic strokes in the second phase [8]. Although the evolution of radiological changes with time has been described in the literature, this case highlights how this may cause confusion in the diagnosis and require caution in evaluating such cases. Normal angiography in the first week may not rule out the disease and a repeat angiography may be warranted if the clinical suspicion of the RCVS is high. Further, our patient had a massive ganglio-capsular regional bleed, which has rarely been mentioned in the medical literature. RCVS commonly presents in the hemorrhagic phase as SAH and cortical bleeds [3]. It may be noted that the presence of a large basal ganglia hemorrhage should not preclude one from considering RCVS as a diagnosis, especially in an appropriate clinical setting such as a post-partum state. The exposure of our patient to tacrolimus further strengthened the associated risk.
Lastly, the high diagnostic utility of intra-arterial milrinone for RCVS has a mere anecdotal mention in the literature [11]. We, however, observed it to have a dramatic role in reversing the vasoconstriction; and thus, it has a remarkable potential for differentiating RCVS from vasculitis. In the medical literature though, angiographic response to intra-arterial vasodilators is varied and there is a lack of strong evidence for the therapeutic role of the same in RCVS [11-14]. Randomized studies conducted on the role of Nimodipine for the same have not shown any significant benefit [15,16]. Thus, our case may be considered as a potential source for conducting further randomized studies in this regard. It would be worthwhile to see if the diagnostic utility of milrinone as observed in our case can be established further with well-designed prospective studies. In conclusion, intra-arterial milrinone appears to have a significant diagnostic utility for RCVS.
Fig. 1. (A) Magnetic resonance imaging of brain showing large intra-parenchymal hematoma involving left ganglio-capsular and frontotemporal regions with significant midline shift. (B) Post-operative computed tomography (CT) scan of brain showing hematoma evacuation. (C) CT angiography demonstrating multifocal luminal irregularities and narrowing (white arrowheads) of distal branches of bilateral middle and posterior cerebral arteries. (D) CT brain on twelfth postoperative day showing multiple acute infarcts (white arrows) in right middle cerebral arteries (MCA) territory. (E) Digital subtraction angiography performed in the second week showing severe proximal narrowing of left MCA (black thick arrow) and the anterior cerebral arteries (ACA) (black thin arrow). (F) Post intra-arterial milrinone injection of left internal carotid artery showing excellent reversibility of MCA and ACA abnormalities.
Fund
None.
Ethics Statement
This study was a case report, ethical approval was not required; however, informed consent was taken from the patient’s close relatives for presenting the patient’s data as a report.
Conflicts of Interest
The authors have no conflicts to disclose.
Author Contribution
Concept and design: PJA, AP, GVK, and KS. Analysis and interpretation: PJA, AP, and GVK. Data collection: PJA and AP. Writing the article: PJA, AP, and KS. Critical revision of the article: PJA, AP, GVK, and KS. Final approval of the article: PJA, AP, GVK, and KS. Overall responsibility: AP. | Recovered | ReactionOutcome | CC BY-NC | 33460536 | 19,025,099 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Corneal oedema'. | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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Acknowledgements
The authors would like to thank the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | AMOXICILLIN\CLAVULANIC ACID, DEXAMETHASONE, OFLOXACIN, TOBRAMYCIN | DrugsGivenReaction | CC BY | 33461505 | 19,654,761 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Corneal pigmentation'. | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | AMOXICILLIN\CLAVULANIC ACID, DEXAMETHASONE, OFLOXACIN, TOBRAMYCIN | DrugsGivenReaction | CC BY | 33461505 | 19,654,761 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Keratitis fungal'. | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | AMOXICILLIN\CLAVULANIC ACID, DEXAMETHASONE, OFLOXACIN, TOBRAMYCIN | DrugsGivenReaction | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ulcerative keratitis'. | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | AMOXICILLIN\CLAVULANIC ACID, DEXAMETHASONE, OFLOXACIN, TOBRAMYCIN | DrugsGivenReaction | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the administration route of drug 'AMOXICILLIN\CLAVULANIC ACID'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the administration route of drug 'DEXAMETHASONE'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Topical | DrugAdministrationRoute | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the administration route of drug 'OFLOXACIN'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Topical | DrugAdministrationRoute | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the administration route of drug 'TOBRAMYCIN'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Topical | DrugAdministrationRoute | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the dosage of drug 'DEXAMETHASONE'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | EYE OINTMENT | DrugDosageText | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the dosage of drug 'OFLOXACIN'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | UNK UNK, QID, DROPS | DrugDosageText | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the dosage of drug 'TOBRAMYCIN'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | EYE OINTMENT | DrugDosageText | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the outcome of reaction 'Corneal oedema'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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Acknowledgements
The authors would like to thank the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33461505 | 19,654,761 | 2021-01-18 |
What was the outcome of reaction 'Corneal pigmentation'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33461505 | 19,654,761 | 2021-01-18 |
What was the outcome of reaction 'Keratitis fungal'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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 the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
What was the outcome of reaction 'Ulcerative keratitis'? | Identification and molecular characterization of Subramaniula asteroides causing human fungal keratitis: a case report.
BACKGROUND
Keratitis due to by filamentous fungi are not easy to diagnose thus causing a delay in correct therapy. There are many descriptions of keratitis due to Candida, Fusarium and Aspergillus genera. Subramaniula genus has only recently been reported to cause human infections and there are few descriptions of eye infections due to this filamentous fungus. Diagnosis of fungal keratitis is usually based on microscopic and cultural techniques of samples obtained by corneal swabbing or scraping. Considering the amount of time required to obtain culture results it is wise to use other diagnostic methods, such as molecular analyses. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. We describe the first case of S. asteroides human keratitis treated with isavuconazole.
METHODS
We describe a rare case of fungal keratitis unresponsive to antimicrobial treatment in a 65-year-old male patient without a history of diabetes or immunological diseases. He reported that the onset of symptoms occurred during a long holiday in Cape Verde Island. Initial treatment with topical antibiotics associated to steroids were ineffective, allowing a slow clinical progression of disease to corneal perforation. On admission in our Hospital, slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae. The slow clinical progression of the disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. Molecular methods used on fungal colonies isolated by Sabouraud's dextrose agar cultures allowed the identification of Subramaniula asteroids from corneal scraping. Antimicrobial test showed a good susceptibility of this filamentous fungus to voriconazole and isavuconazole. Moreover, this fungal keratitis was successfully treated with isavuconazole, without side effects, observing a progressive clinical improvement.
CONCLUSIONS
Molecular methods may be useful for the identification of filamentous fungal keratitis on scraping samples thus shortening the time of diagnosis. Systemic therapy by isavuconazole could be useful to treat the filamentous fungal keratitis, reducing the possible adverse effects due to the use of voriconazole by systemic administration.
Background
Fungal keratitis (FK) is considered responsible for 30–60% of infectious keratitis in humans with serious damage to vision that often require corneal restroom surgeries, and sometimes, corneal transplantation, enucleation or evisceration [1–3].. They have become more frequent over the last four decades favoured by conditions such as diabetes, chronic ocular diseases, immuno-compromised patients, increased use of contact lens, topical steroids and antibacterial drugs, as well as an increase in surgical procedures [1, 2, 4–6].
FKs can be mainly caused by Candida, Fusarium and Aspergillus species [1, 3, 7]. Usually, FK is due to fungal access into the corneal stroma through a defect in the epithelium and trauma represents a frequent event. Diagnosis of fungal keratitis is commonly based on standard methods such as microscopic and cultural techniques of samples obtained by corneal swabbing. Identification of filamentous moulds is based mostly on microscopic examination of sporulating colonies. These methods could result inadequate in confirming a fungal agent, because fungi penetrate deeper layers of the cornea. Moreover, corneal culture is scarcely sensitive and requires long growth times, usually taking 1 to 35 days, especially when an antibiotic resistance test should be performed. In vivo confocal microscopy may be a helpful clinical adjunct but is still not available everywhere and lacks sufficient resolution to identify fungal hyphae [8, 9].
Molecular methods have been developed, demonstrating their usefulness as a rapid, highly sensitive and accurate diagnostic tool [10], though the latter are not easy and limited to only a few laboratories that are able to use these techniques. To avoid negative results due to deep infiltrates, corneal scrapings are recommended, and these samples should be analysed by traditional and molecular techniques. Direct-PCR on biological sample is highly sensitive and could be considered a good method for FK diagnosis as it reduces the time needed, taking 2 to 3 h. The obstacle to using PCR is that it requires very specialized equipment that may not always be available. Therefore, Kuo et al. [11] suggested implementing a dot hybridizaton assay, which is highly sensitive and can detect a wide variety of fungi. This assay used PCR to first amplify the highly conserved fungal 5.8S rRNA gene before adding it to immobilized oligonucleotide probes specific for fungi fixed to a nylon membrane. Detection by this dot assay, which could be seen with the naked eye, was reported to have been 100% sensitive and 96.7% specific for fungi identification.
FKs treatment is difficult because the diagnosis is often delayed and no antifungal drugs for topical eye use are commercially available; most used topical galenic antifungals often fail to achieve an adequate control of keratitis. Once fungi reach the deep stroma, they can penetrate into the anterior chamber and there is a high risk of endophthalmitis that can lead to ocular enucleation. One study suggested early deep anterior lamellar keratoplasty as a possible safe therapeutic approach to effectively eradicate fungal keratitis affecting the optic zone and poorly responsive to medical treatment, thus avoiding corneal transplant [12]. Therapeutic options against these fungi are limited by low tissue penetration in the eye due to ocular barriers. Most of the inside of the eye lacks blood vessels and the outer and inner blood-retinal barrier, which limits the influx of drugs into the retina and vitreous regions, requires the systemic administration of high doses to achieve therapeutic concentrations within the eye. Moreover, blinking and tear film turnover limits the residence time of a drug and the access to the deeper structures of the eye is hindered by corneal epithelium and stroma with varying lipophilicity.
We report a rare case of keratitis due to Subramaniula asteroides [13] in a patient without co-morbidities and with no reported eye trauma, identified by molecular methods and successfully treated with systemic isavuconazole associated to topic voriconazole.
Case presentation
A 65-year-old male patient without a history of diabetes or immunological diseases presented to the Emergency Unit of University Hospital S. Anna of Ferrara, Italy, with photophobia and ocular pain in the left eye. The patient had just returned from a long holiday in Cape Verde and he reported that the onset of symptoms had occurred about 20 days earlier with the sensation of a foreign body in the eye, without any previous ocular trauma. In a Medical Centre of Cape Verde Island, he was diagnosed with a keratitis in the left eye, initially treated with tobramycin 0.3% and dexamethasone 0.1% eye ointment for a week, then discontinued because of the worsening of his condition. Then oral amoxicillin 875 mg and clavulanic acid 125 mg tid and topical ofloxacin 0.3% eye drops qid were administered for the following 10 days. Since the symptoms were more severe and the visual acuity reduced, the patient decided to return to Italy.
On admission to our Hospital the best correct visual acuity was 20/200 at distance in the left eye. Slit-lamp examination of the left eye showed conjunctival congestion and hyperemia, a large inferior corneal ulceration with brown pigment, corneal edema, about 3 mm of hypopyon and irido-lenticular synechiae (Fig. 1). The posterior segment was not visible, ultrasonography did not show any sign of intraocular infection. Corneal scrapings were obtained for microbiological analyses. Sample obtained by scraping was directly inoculated onto chocolate agar plate (Vacutest® KIMA) and sent to the Clinical Microbiology Laboratory of University Hospital of Ferrara and incubated at 37 °C with 5% of CO2 atmosphere.
Fig. 1 a Slit lamp picture taken on initial presentation in our Hospital showing an inferior corneal ulceration with brown pigment (red arrow) and about 3 mm of hypopyon (yellow arrow) in the left eye. b Anterior segment optical coherence tomography (AS-OCT) showing the depth of the ulcer (white arrow)
Since the clinical picture was suggestive of a fungal keratitis, pending the outcome of microbiological tests, the patient immediately started treatment with fortified topical tobramycin 14 mg/ml qid, moxifloxacin 0.5% eye drops qid, cyclopentolate 1% tid and voriconazole 1% every 2 hours [14]. In addition, oral voriconazole was administered at the loading dose of 400 mg bid on days 1 and 2 and subsequently at the dose of 200 mg bid from day 3. Blood cell count and liver and kidney function blood tests were monitored every 15 days.
Forty-eight hours after corneal scraping fungi colonies were observed without any bacterial growth. Microscopic examination evidenced hyaline filamentous forms with clear mycelium. Growth was shown at 30 °C and 37 °C after 1 week of incubation on Chocolate Agar plate (CHOC), BCG agar plate, and Sabouraud Dextrose Agar plate (Fig. 2a,b,c). Microscopic observation showed hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal (Fig. 2d, e, f, g).
Fig. 2 Macroscopic view colonies after one week of incubation on: a Chocolate Agar plate (CHOC); b BCG agar plate; c Sabouraud Dextrose Agar plate; d-g Microscopic view 0,25% Lugol stain. Microscopic description: hyphae broad, septate, hyaline, turning dark brown with age. Conidiophores phialidic, terminal or intercalary, short, hyaline, obclavate or cylindrical. Conidia hyaline, unicellular, obovoidal or ellipsoidal
Cultured samples on Sabouraud’s agar plates were sent to the Laboratory of Mycology at Policlinico “A. Gemelli” of the Catholic University of Rome for biomolecular analyses to identify the filamentous fungus obtained by cultures [15, 16].
Molecular methods allowed the identification of Subramaniula asteroides by fungal DNA extraction (using Plant extraction kit, Qiagen®), PCR amplification of β-tubulin gene (βtub) by specific primers and Sanger sequencing method of fungal gene [13, 17, 18]. PCR products were sequenced and compared in GenBank database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The βtub sequence shared 99% identity with the reference sequence (KP900696.1) for Subramaniula asteroides (Strain CBS 128679).
Antifungal susceptibility testing on the case strain was performed by broth micro-dilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, Thermo Scientific) [10]. This test showed a low minimal inhibitory concentration (MIC) of S. asteroides for isavuconazole and the other triazoles, echinocandins and amphotericin B (Table 1).
Table 1 Susceptibility of Subramaniula asteroides to antifungal drugs tested
Antifungal drugs MIC
Amphotericin B 0.25
Anidulafungin 0.125
Caspofungin 0.5
Micafungin 0.125
Voriconazole 0.06
Posaconazole 0.06
Itraconazole 0.06
Isavuconazole 0.06
Antifungal susceptibility testing on the case strain was performed in triplicate by broth microdilution according to CLSI methods for filamentous fungi (Sensititre™ YeastOne ITAMYUCC, a modified panel YO10 with isavuconazole instead of 5-fluorocytosine, Thermo Scientific). Sensititre YeastOne was tested for efficacy in Aspergillus spp. and non-Aspergillus molds MIC valuation as previously described [19–21]. MIC values of the triazoles for Candida krusei ATCC 6258, A. fumigatus ATCC MYA-3626, and A. flavus ATCC 204304, which were used as quality control isolates, were all within the expected ranges (data not shown). The MICs of the antifungal drugs amphotericin B, anidulafungin, caspofungin, micafungin, voriconazole, posaconazole, itraconazole, isavuconazole were 0.25, 0.125, 0.5, 0.125, 0.06, 0.06, 0.06, 0.06 μg/mL, respectively (Table 1). Unfortunately, there are no clinical breakpoints available for Subramaniula asteroides. However, CLSI epidemiological cutoff values for antifungal susceptibility testing for Aspergillus spp. have recently been released [22]. Regarding these molds, the document shows ECV (μg/mL) of amphotericin B, caspofungin, isavuconazole, itraconazole, posaconazole, voriconazole.
Due to the scarce improvement of the keratitis and considering the inability to determine the ocular tissue concentration levels of the drugs in the patient, voriconazole was stopped and isavuconazole was started at the loading oral dose of 200 mg tid for the first 48 h, continuing with 200 mg per day. Ten days later, hypopyon had been reduced and symptoms were improved. Over the next 4 weeks the cornea had epithelized, and the inflammation was solved. Oral isavuconazole, topical antimicrobials and cyclopentolate were discontinued after 6 weeks.
The fungal corneal ulcer due to S. asteroides was successfully treated; the best correct visual acuity 2 months after treatment was 20/50 with a residual corneal scar (Fig. 3). Periodic eye tests showed a progressive improvement.
Fig. 3 Two months after treatment non signs of active infection. A residual para-central corneal scar (white arrow) limits the visual acuity to 20/50
Discussion and conclusion
Filamentous fungi may be implicated in fungal keratitis in humans, which is particularly widespread in tropical countries. It is very important that a specific diagnosis be made as quickly as possible to ensure a prompt institution of adequate antifungal therapy.
Aspergillus spp. and Fusarium spp. are the most common species responsible for human keratitis. We report a first case of keratitis due to S. asteroides treated with isavuconazole. S. asteroides is a filamentous fungus present in the natural environment and strongly associated with traumatic eye injury or skin infections [13, 18]. Subramaniula asteroides belongs to the phylum Ascomycota, family Chaetomiaceae and genus Subramaniula. The members of this family are ascosporulating fungi. The Chaetomiaceae (Subramaniula asteroids, Subramaniula obscura and mainly Chaetomium anamorphosum) were considered opportunistic pathogens rarely causing skin infections and keratitis due to their ability to grow at high temperatures [18]. Apart from these reports, the role of this fungus as a human pathogen is largely ignored.
In our case, the slow clinical progression of disease to corneal perforation and the aspect of the ulcer were consistent with a mycotic etiology. The patient was initially treated with a topical antibiotic associated to a steroid. Because of the poor response, further treatments were prescribed with prolonged cycles of topical antibiotics and steroids without any benefits and consequent loss of the visual acuity. Corneal scraping performed at the Ophthalmologic Clinic allowed the identification of filamentous moulds by preliminary microscopic examination. There are findings that the delay of diagnosis could require surgical treatment up to the point of an eventual ocular evisceration, as described in Fusarium spp. keratitis [7].
Only molecular techniques allowed the exact identification of S. asteroides as responsible for keratitis. Previous reports of S. asteroids human infections are described in a case of endophthalmitis in a patient with non-insulin dependent diabetes mellitus after an eye trauma treated with topical amphotericin B deoxycholate in combination with fluconazole for 42 days [14], in a male patient with sinusitis without other disorders [14], and in a case of keratitis by S. asteroides after a corneal trauma [23].
This is to our knowledge the first case of S. asteroides human keratitis treated with isavuconazole. This drug was able to eradicate the infection of S. asteroides keratitis after a poor response to a first course of voriconazole. Prolonged topical voriconazole treatment in fungal keratitis can induce ocular surface dysplasia [24]. Moreover, patients who received voriconazole had a corneal perforation or required therapeutic penetrating keratoplasty [25]. Isavuconazole was well tolerated, confirming the data of less hepatobiliary, eye and skin disorders. The favourable outcome allows us to hypothesize that the ocular concentration of isavuconazole is sufficient to eradicate the fungal infection, as suggested by Schmitt-Hoffmann A. in a study about the tissue concentrations of isavuconazole in the eye and in the lacrimal glands of rats [26]. Unlike the other azoles, to our knowledge there are no data regarding the concentration of isavuconazole in the human eye.
Abbreviations
tidTer in die
qidQuarter in die
S. asteroidesSubramaniula asteroides
MICMinimal inhibitory concentration
Btubβ-tubulin gene
CLSIClnical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087, USA
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors would like to thank the patient and all members of the study team, with a particular reference to the Clinical Pharmacy, the Laboratory of Clinical Microbiology of University ‘S. Anna’ Hospital of Ferrara and the Laboratory of Mycology of Policlinico Universitario “A. Gemelli” IRCCS.
Authors’ contributions
All authors contributed to the study conception and design. RC and MS performed the methodology. PP and CS performed the collection of ocular samples. AM followed the ophthalmological treatment. DS performed material preparation. GC performed microbiological cultures and microscopic identification and RT performed molecular analyses and antifungal susceptibility testing. RC was a major contributor in writing the manuscript and all authors commented on previous versions of the manuscript. Writing - review and editing were performed by RC and MS. All authors read and approved the final manuscript. This manuscript has not been published and is not under consideration for publication elsewhere.
Funding
All authors state, that for this work, there was no funding.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files. The datasets used during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Not applicable. This type of study does not require approval by our Ethics Committee.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Competing interests
The authors declare that they have no competing interests. | Recovering | ReactionOutcome | CC BY | 33461505 | 19,614,480 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Device related infection'. | Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma.
Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.
The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.
In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.
Background
Thrombotic microangiopathy (TMA) is a rare cause of anemia in multiple myeloma (MM) patients, but can occasionally be elicited by common anti-myeloma drugs, especially by proteasome-inhibitors (PI) like carfilzomib (CFZ) [1–3]. Reports about TMA in MM induced by CFZ and optimal therapeutic approaches are scarce. Recently, single case reports described successful treatment of TMA in MM with the terminal complement pathway inhibitor eculizumab [1, 2, 4–6]. Definitive treatment recommendations, however, are lacking. Below we describe two cases of CFZ-induced TMA, that were successfully treated by eculizumab and provide evidence about precise therapeutic work-flow and possible interventions.
Case 1
A 43-year old male patient was diagnosed with IgG-kappa-MM in August 2018. At admission, we found extensive osteolysis and an acute kidney failure with a serum-creatinine of 4.2 mg/dl [0.67–1.17] (GFR 15 ml/min; MDRD) without previous history of impaired kidney function. With highly elevated serum free kappa light chains (kappa-SFLC) 3645 mg/l [0.35–15.10] and 4.2 g/d [< 0.15] urinary protein excretion, in the absence of albuminuria, cast nephropathy was assumed as the most likely cause of acute kidney failure. Since there was no sign of further organ injury, amyloidosis seemed unlikely, as well MIDD (monoclonal immunoglobulin deposition disease), which is often accompanied by amyloidosis and presents with albuminuria. The type of renal injury was not further determined by kidney puncture. The M-protein was elevated with 37 g/l, IgG 52.3 g/l [6.1-16.16], k/l-ratio 864 [0.46-4], hemoglobin (Hb) 9.5 g/dl [13.5–17.5], β2-microglobulin 8.7 mg/dl [0-2.34], serum calcium and LDH were normal. The bone marrow plasma cell (BMPC) infiltration was 15%, FISH excluded high-risk cytogenetics. Following the ISS grading system, we diagnosed an IgG-kappa-MM stage III (Durie & Salmon stage IIIB) and symptomatic myeloma with 3/4 CRAB criteria (anemia, renal impairment, bone lesions). The revised myeloma comorbidity index (R-MCI: 1/9 = fit/low-risk) revealed a fit patient [7–9]. Due to the CRAB-criteria, specifically renal impairment, chemotherapy was initiated with one cycle of bortezomib, doxorubicin, dexamethasone (BAD) followed by two cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) after improvement of the kidney function and resolved urinary proteinuria. Since M-protein reduction was insufficient (21.4 g/l), the regimen was switched a second time to CFZ, lenalidomide and dexamethasone (KRd). After two cycles KRd, a partial remission (PR; M-protein 5.3 g/l, IgG 6.4 g/l) was achieved and high-dose melphalan (200 mg/m²) chemotherapy with autologous stem cell transplantation (ASCT) was performed. On day (d) 42 post ASCT IgG levels were increasing again (21.1 g/l). Based on the distinct improvement of the myeloma markers after KRd and a missing additional response to ASCT, our MM-tumor board decided to apply three consolidation cycles of KRd. In May 2019, the 3rd KRd cycle (1st consolidation cycle after ASCT) was initiated. At d2 of CFZ, the patient developed fever, dyspnea and malaise. Platelets were 11Tsd/µl, Hb 10.8 g/dl, LDH 1836U/l, haptoglobin < 150 mg/l, unconjugated bilirubin 2.7 mg/dl, the creatinine rose from 0.72 to 2.07 mg/dl [0.67–1.17] (GFR > 60 to 35 ml/min) (Fig. 1a) and urinary proteinuria increased from normal values to 52 g/l [< 0.135]. In the peripheral blood smear, 11‰ schistocytes were detected and an altered complement profile with reduced C3 and C4 levels was found (C3 77.6md/dl, C4 9.9 mg/dl). TMA-Index (LDH/platelets ratio) was elevated to 166. These findings (schistocytes > 10‰, elevated creatinine and TMA-Index) have been described as poor prognostic factors for transplant associated-TMA (TA-TMA) [10]. Of note, two days earlier, lab results had been normal (Fig. 1a). Chest CT scan showed bilateral infiltrates, matching pulmonary hemorrhage (Fig. 2). Due to the acute development of hemolysis, together with acute kidney injury, unsuspicious ATAMTS13 activity (61%) [50–110], normal ADAMTS13 antigen (0.48 IU/ml) [0.35–1.2] and direct Coombs test being negative, we suspected medication-induced TMA. Therapeutic plasma exchange (TPE) was initiated by replacement with fresh frozen plasma (FFP) on a daily regimen and on account of declining kidney function with development of acute kidney injury stage 3 according to the acute Kidney Injury Network (AKIN), dialysis was necessary one day later. After six days of TPE neither LDH nor platelets improved. Assuming CFZ-induced TMA, we administered eculizumab (900 mg) along with meningococcal vaccination and initiation of antibiotic prophylaxis. Five days later, LDH declined to 818U/l and platelet counts improved to 58Tsd/µl without transfusions. We continued eculizumab (900 mg) weekly. After the fourth application, dialysis could be discontinued. Platelet counts normalized within two months after treatment initiation of eculizumab and there were no further signs of TMA, thus eculizumab was terminated (Fig. 1a). One year after TMA diagnosis and KRd consolidation, our patient remains in PR of his MM and CR of the CFZ-induced TMA.
Fig. 1 Course of CFZ-TMA in the two patients. a Case #1: This patient developed acute kidney injury, fever and pulmonary hemorrhage during the first consolidation with carfilzomib, lenalidomide and dexamethasone (KRd) after ASCT. Laboratory findings (thrombocytopenia) and schistocytosis of 11‰ were consistent with thrombotic microangiopathy (TMA). Therapeutic plasma exchange (TPE) was immediately initiated, but shortly after dialysis was necessary. As blood values did not improve, we finally administered eculizumab for a total of seven doses and saw a rapid response in LDH, platelet number and kidney function with our patient being still in PR. b Case #2: This patient, who is treated in the DSMM XVII study (Arm A: Elotuzumab-KRd) developed head ache, malignant hypertension and laboratory distortions (thrombocytopenia, increase of LDH and acute kidney injury) consistent with TMA. After a short period of TPE, eculizumab was infused (total of six infusions). Blood values improved but kidney function remains decreased
Fig. 2 a Chest-CT in patient case 1, d1 of CFZ-TMA onset: Bipulmonary extensive ground-glass opacities in all lung fields, mostly omitting the periphery and predominantly occurring in the right lung. b Mechanism of CFZ-TMA: Within the proximal complement activation C3 is cleaved by the C3 convertase to anaphylactic 3a and C3b. C3b then cleaves C5 to C5a and C5b, the latter together with C6-C9 forming the membrane attack complex (MAC) within the terminal pathway. Activity of the C3 convertase is regulated by complement factor H and regulated proteins. Proteasome inhibition blocks CFH [11]. The monoclonal antibody eculizumab counteracts the resulting overactivation of C3b by binding C5
Case 2
The second 59-year-old male patient was diagnosed with IgG-kappa-MM in 11/2018. CT scan revealed osteolysis of the sacrum, pelvis and vertebrae. Calcium and creatinine were normal and the Hb was slightly decreased (13.3 g/dl). IgG was 38.4 g/l, k-SFLC 182 mg/l, k/l-ratio 60.5. BM biopsy revealed 40% PC infiltration. Cytogenetics were favorable (trisomy 5p15, 9q22, 11q13 und 15q22). The ISS and R-ISS were both I, Durie & Salmon stage was IIIA and symptomatic MM was diagnosed with 1/4 CRAB symptoms. The patient was classified as fit for ASCT (R-MCI-score: 2/9 = fit) [7–9]. We included the patient into the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Induction with elotuzumab, CFZ, lenalidomide and dexamethasone (E-KRd, 6 cycles) and ASCT with melphalan 200 mg/m2 were performed and due to repeated respiratory infections (boca- and corona (CoV NL 63) virus) dose reductions of elotuzumab and lenalidomide were executed. Before ASCT, kappa-SFLC decreased to 12.8 mg/l (vgPR).
In 01/20, within the last (4th) cycle of E-KRd consolidation, the patient developed fever and acute kidney failure with creatinine 1.7 mg/dl (GFR 40 ml/min, MRDRD; baseline-creatinine: 1 mg/dl). Prerenal genesis was assumed (fractional sodium excretion < 1%) and fluids were infused. However, creatinine elevation did not resolve finally reaching acute kidney injury stage 3 according to AKIN and proteinuria reached 6.2 g/d. The patient developed headache and high blood pressure (BP 220/105 mmHg). Platelets and Hb gradually decreased (Fig. 1b), haptoglobin was < 5 mg/dl. In the peripheral blood smear, 44‰ schistocytes were visible; ADAMTS13 activity and antigen were normal (58% and 0.40 IU/ml, respectively) and Coombs test negative. Blood culture additionally showed Staphylococcus epidermidis due to port infection and throat swab detected influenza A (H3N2) and B.
Since TMA was diagnosed (LDH/platelets ratio 88.3), high-dose glucocorticoids and TPE were applied (before completion of diagnostics). Without substantial improvement, five days after first plasmapheresis our patient received eculizumab (Fig. 1b), starting at 900 mg. A total of 11 sessions of plasma exchange at a daily basis were performed with FFP as replacement (Fig. 1b). Parameters of hemolysis rapidly improved, so that glucocorticoids could be expeditiously reduced and eculizumab was terminated after four cycles with 900 mg/weekly and two doses with 1200 mg/every two weeks (Fig. 1b).
In 05/19, the patient showed VGPR of his MM, the BMPC infiltration even CR (polyclonal PCs of 5%) and gradual renal function improvement (eGFR improved from 10 to 32 ml/min). Maintenance therapy with reduced doses of elotuzumab-lenalidomide (E-R: lenalidomide with 5 mg d1-28) was successfully initiated and TMA has remained in CR.
Discussion and conclusion
Hemolysis is a rather rare cause for anemia in MM [12]. When anemia is accompanied with thrombocytopenia, acute kidney injury, high blood pressure, neurological or unexplained extrarenal symptoms TMA should be considered. TMA includes a group of etiologically diverse diseases: Primary TMA, which include atypical HUS (aHUS) or thrombotic thrombocytopenic purpura (TTP) and secondary TMA and infection-associated TMA, involving Shiga-toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) [6, 13, 14]. TTP, in contrast to other TMA forms, is defined by decreased activity of the vWF-cleaving enzyme ADAMTS13 [6]. Unlike “typical” HUS, which is triggered by infections with STEC, complement mediated TMA is driven by uncontrolled complement activation and affected patients frequently harbor mutations in complement regulatory proteins (Fig. 2b) [15]. Secondary TMA is elicited by medication, malignancy, pregnancy, malignant hypertension, transplantations, infections or associated to autoimmune diseases [6, 10, 12–14]. As reviewed recently [6], TMA in MM can be elicited by ASCT- or allogeneic-SCT, MM progression, or anti-myeloma therapy. Drug-induced TMA (DITMA) may occur in MM due to PIs bortezomib or CFZ [3, 16, 17]. CFZ-TMA can appear early after onset of the drug, but also as late as two years after first administration [1, 2]. CFZ-TMA is probably driven by complement activation of the alternative pathway in terms of complement-mediated TMA [2–4, 18]. Blasco et al. described three cases in which plasma samples from patients with CFZ-TMA, led to depositions of complex membrane attack complex (C5b-9) of on endothelial cells, suggesting a complement overactivation [4]. Supporting this assumption, proteasome inhibition has been found to block Factor H, consequently leading to complement activation (Fig. 2b) [11]. Bortezomib-induced cases of TMA are attributed to decreased activity of ADAMTS13 [19, 20]. However, the majority of bortezomib-induced cases of TMA/TTP had only slightly decreased ADAMTS13 activity and PI-induced TMA in MM might be generally based on pathological overactivation of the alternative complement pathway rather than TTP [6]. In patient #2, TMA was either induced by CFZ or influenza A or B [15, 21]. Also a combination of both preexistent vascular endothelial injury due to CFZ and transient complement activation during influenza infection was eagerly discussed within our group. In this respect, eculizumab could be effective in patients treated with concurrent PI treatment, infection and TMA.
In patient #2, in contrast to patient #1, C3 and C4 levels were normal; CH50 and C5b-9, the terminal pathway of the complement pathway were, however, not assessed. The fast response to eculizumab and the lacking effect of TPE seemed to argue for pathological complement activation, but it cannot be ruled out that the classical or the alternative complement pathway was involved. Importantly, both patients developed TMA several weeks after ASCT. Since TA-TMA was described to occur in a complement-dependent manner, like complement mediated TMA [10], a combination of TMA-triggers is likewise conceivable.
Taken together, several factors might have induced TMA in our patients: ASCT, genetic predispositions, viral infections and the underlying CFZ treatment. Thus, definite causality could ot be entirely proven. The major criticism of our study may be missing additional in vitro studies of complement activation and the unavailability of renal biopsies for further diagnostics. Kidney biopsies had been discussed interdisciplinary in our weekly MM tumor board, however, in the acute clinical setting, the potential biopsy risk, especially bleeding, was judged to outweigh potential benefits and on top, both patients had declined kidney biopsies.
In respect to therapy for TMA in MM, definitive clinical practical guidelines do not exist [6]. For DITMA, the causative drug must be discontinued promptly, high-dose glucocorticoids are given and plasmapheresis is performed [2, 6]. In CFZ-TMA, successful treatment with eculizumab, a terminal complement pathway inhibitor, was described in six cases to our knowledge [1, 2, 4, 5, 22]. Nevertheless, reports of TMA in MM remain scarce, and the definitive treatment regimen as well as definitive duration of treatment are unclear [6]: Portuguese and Lipe (2018), Moliz et al. (2019) and Blasco et al. (2020) administered eculizumab for up to three weekly doses [2, 4, 22], whereas Bhutani et al. (2020) for four months [1]. In our two cases, only after eculizumab initiation, hemolysis and creatinine levels improved impressively (Fig. 1A,B), plus the application period of two months of eculizumab was efficient without relapsing TMA, thus appears possible to be shorter than four months. On the other hand a shorter treatment period, as reported by Portuguese and Lipe, might be insufficient as one of their eculizumab-treated patients stayed on hemodialysis with this regime [22].
TPE is generally recommended for TMA. Plasma exchange, however, is not without side effects, and can remove therapeutic antibodies from the circulation, thus its concurrent use is not recommended [6, 10]. Interestingly, in our cases the success of eculizumab was not fully dependent on the termination of TPE, since in patient #2 TPE was continued during the first two eculizumab doses. In this respect, concerns, that TPE would remove eculizumab from the blood or restore C5-levels available for activation, seem unfounded. On the other hand, a significant improvement of creatinine-levels and platelets was only achieved after termination of TPE in patient #2 (Fig. 1B). Thus, irrespective of the cause of TMA in MM patients under PI treatment or shortly after ASCT, eculizumab rather than TPE could be considered as standard first-line therapy [2, 6] (Fig. 3). Increased susceptibility to meningococcal infection during eculizumab treatment has to be considered and vaccination should be implemented [23]. As soon as ADAMTS13 activity is proven to be within the normal range (50–150%) and TTP is excluded, further treatment decisions can be drawn [6]. Additionally, in our experience short-term use of eculizumab was sufficient for effective TMA treatment. Furthermore, eculizumab treatment did not worsen MM parameters in neither of our patients.
Fig. 3 Guideline for diagnostic and therapeutic approach for TMA in MM: Whenever clinical and laboratory findings are consistent with TMA, one should rapidly terminate possible causative drugs, initiate therapeutic plasma exchange (TPE) and apply a first dose of eculizumab. As soon as ADAMTS13 activity is determined further therapeutic decisions can be drawn
Taken together, CFZ-induced TMA is a serious event and should be assumed in treated MM patients with rapid acute kidney failure and hemolysis. Fast treatment initiation with eculizumab can reverse pathological complement system activation and prevent organ damage. As shown in our patients, early initiated, short-term treatment with eculizumab can sufficiently terminate CFZ-TMA and counteract TMA-poor prognostic factors.
Abbreviations
aHUSAtypical hemolytic uremic syndrome
AKINAcute kidney injury network
ASCTAutologous stem cell transplantation
BMBone marrow
CFZ-TMACarfilzomib-induced thrombotic microangiopathy
CRComplete response
DITMADrug-induced thrombotic microangiopathy
FFPFresh frozen plasma
TMAThrombotic microangiopathy
TPETherapeutic plasma exchange
TTPThrombotic thrombocytopenic purpura
MMMultiple myeloma
PCPlasma cell
PIProteasome inhibitor
STECShiga-toxin-producing E.coli
vgPRVery good partial response
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Michael Rassner, Rebecca Baur, Andreas Mackensen and Monika Engelhardt contributed equally to this work.
Acknowledgements
We would like to thank both patients for consent of publication of their educational cases within this work.
Authors’ contributions
MR and RB treated the patients, drafted and wrote the manuscript; JS, MS and RW treated the patient and revised the manuscript; AM and ME treated the patient, initiated and wrote the manuscript. All authors read and approved the final manuscript.
Funding
There was no funding received to support this research. Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
We have obtained written consent for publication from both patients presented in this case report.
Competing interests
The authors declare that they have no competing interests. | CARFILZOMIB, DEXAMETHASONE, ELOTUZUMAB, LENALIDOMIDE | DrugsGivenReaction | CC BY | 33461512 | 18,819,690 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Influenza A virus test positive'. | Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma.
Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.
The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.
In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.
Background
Thrombotic microangiopathy (TMA) is a rare cause of anemia in multiple myeloma (MM) patients, but can occasionally be elicited by common anti-myeloma drugs, especially by proteasome-inhibitors (PI) like carfilzomib (CFZ) [1–3]. Reports about TMA in MM induced by CFZ and optimal therapeutic approaches are scarce. Recently, single case reports described successful treatment of TMA in MM with the terminal complement pathway inhibitor eculizumab [1, 2, 4–6]. Definitive treatment recommendations, however, are lacking. Below we describe two cases of CFZ-induced TMA, that were successfully treated by eculizumab and provide evidence about precise therapeutic work-flow and possible interventions.
Case 1
A 43-year old male patient was diagnosed with IgG-kappa-MM in August 2018. At admission, we found extensive osteolysis and an acute kidney failure with a serum-creatinine of 4.2 mg/dl [0.67–1.17] (GFR 15 ml/min; MDRD) without previous history of impaired kidney function. With highly elevated serum free kappa light chains (kappa-SFLC) 3645 mg/l [0.35–15.10] and 4.2 g/d [< 0.15] urinary protein excretion, in the absence of albuminuria, cast nephropathy was assumed as the most likely cause of acute kidney failure. Since there was no sign of further organ injury, amyloidosis seemed unlikely, as well MIDD (monoclonal immunoglobulin deposition disease), which is often accompanied by amyloidosis and presents with albuminuria. The type of renal injury was not further determined by kidney puncture. The M-protein was elevated with 37 g/l, IgG 52.3 g/l [6.1-16.16], k/l-ratio 864 [0.46-4], hemoglobin (Hb) 9.5 g/dl [13.5–17.5], β2-microglobulin 8.7 mg/dl [0-2.34], serum calcium and LDH were normal. The bone marrow plasma cell (BMPC) infiltration was 15%, FISH excluded high-risk cytogenetics. Following the ISS grading system, we diagnosed an IgG-kappa-MM stage III (Durie & Salmon stage IIIB) and symptomatic myeloma with 3/4 CRAB criteria (anemia, renal impairment, bone lesions). The revised myeloma comorbidity index (R-MCI: 1/9 = fit/low-risk) revealed a fit patient [7–9]. Due to the CRAB-criteria, specifically renal impairment, chemotherapy was initiated with one cycle of bortezomib, doxorubicin, dexamethasone (BAD) followed by two cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) after improvement of the kidney function and resolved urinary proteinuria. Since M-protein reduction was insufficient (21.4 g/l), the regimen was switched a second time to CFZ, lenalidomide and dexamethasone (KRd). After two cycles KRd, a partial remission (PR; M-protein 5.3 g/l, IgG 6.4 g/l) was achieved and high-dose melphalan (200 mg/m²) chemotherapy with autologous stem cell transplantation (ASCT) was performed. On day (d) 42 post ASCT IgG levels were increasing again (21.1 g/l). Based on the distinct improvement of the myeloma markers after KRd and a missing additional response to ASCT, our MM-tumor board decided to apply three consolidation cycles of KRd. In May 2019, the 3rd KRd cycle (1st consolidation cycle after ASCT) was initiated. At d2 of CFZ, the patient developed fever, dyspnea and malaise. Platelets were 11Tsd/µl, Hb 10.8 g/dl, LDH 1836U/l, haptoglobin < 150 mg/l, unconjugated bilirubin 2.7 mg/dl, the creatinine rose from 0.72 to 2.07 mg/dl [0.67–1.17] (GFR > 60 to 35 ml/min) (Fig. 1a) and urinary proteinuria increased from normal values to 52 g/l [< 0.135]. In the peripheral blood smear, 11‰ schistocytes were detected and an altered complement profile with reduced C3 and C4 levels was found (C3 77.6md/dl, C4 9.9 mg/dl). TMA-Index (LDH/platelets ratio) was elevated to 166. These findings (schistocytes > 10‰, elevated creatinine and TMA-Index) have been described as poor prognostic factors for transplant associated-TMA (TA-TMA) [10]. Of note, two days earlier, lab results had been normal (Fig. 1a). Chest CT scan showed bilateral infiltrates, matching pulmonary hemorrhage (Fig. 2). Due to the acute development of hemolysis, together with acute kidney injury, unsuspicious ATAMTS13 activity (61%) [50–110], normal ADAMTS13 antigen (0.48 IU/ml) [0.35–1.2] and direct Coombs test being negative, we suspected medication-induced TMA. Therapeutic plasma exchange (TPE) was initiated by replacement with fresh frozen plasma (FFP) on a daily regimen and on account of declining kidney function with development of acute kidney injury stage 3 according to the acute Kidney Injury Network (AKIN), dialysis was necessary one day later. After six days of TPE neither LDH nor platelets improved. Assuming CFZ-induced TMA, we administered eculizumab (900 mg) along with meningococcal vaccination and initiation of antibiotic prophylaxis. Five days later, LDH declined to 818U/l and platelet counts improved to 58Tsd/µl without transfusions. We continued eculizumab (900 mg) weekly. After the fourth application, dialysis could be discontinued. Platelet counts normalized within two months after treatment initiation of eculizumab and there were no further signs of TMA, thus eculizumab was terminated (Fig. 1a). One year after TMA diagnosis and KRd consolidation, our patient remains in PR of his MM and CR of the CFZ-induced TMA.
Fig. 1 Course of CFZ-TMA in the two patients. a Case #1: This patient developed acute kidney injury, fever and pulmonary hemorrhage during the first consolidation with carfilzomib, lenalidomide and dexamethasone (KRd) after ASCT. Laboratory findings (thrombocytopenia) and schistocytosis of 11‰ were consistent with thrombotic microangiopathy (TMA). Therapeutic plasma exchange (TPE) was immediately initiated, but shortly after dialysis was necessary. As blood values did not improve, we finally administered eculizumab for a total of seven doses and saw a rapid response in LDH, platelet number and kidney function with our patient being still in PR. b Case #2: This patient, who is treated in the DSMM XVII study (Arm A: Elotuzumab-KRd) developed head ache, malignant hypertension and laboratory distortions (thrombocytopenia, increase of LDH and acute kidney injury) consistent with TMA. After a short period of TPE, eculizumab was infused (total of six infusions). Blood values improved but kidney function remains decreased
Fig. 2 a Chest-CT in patient case 1, d1 of CFZ-TMA onset: Bipulmonary extensive ground-glass opacities in all lung fields, mostly omitting the periphery and predominantly occurring in the right lung. b Mechanism of CFZ-TMA: Within the proximal complement activation C3 is cleaved by the C3 convertase to anaphylactic 3a and C3b. C3b then cleaves C5 to C5a and C5b, the latter together with C6-C9 forming the membrane attack complex (MAC) within the terminal pathway. Activity of the C3 convertase is regulated by complement factor H and regulated proteins. Proteasome inhibition blocks CFH [11]. The monoclonal antibody eculizumab counteracts the resulting overactivation of C3b by binding C5
Case 2
The second 59-year-old male patient was diagnosed with IgG-kappa-MM in 11/2018. CT scan revealed osteolysis of the sacrum, pelvis and vertebrae. Calcium and creatinine were normal and the Hb was slightly decreased (13.3 g/dl). IgG was 38.4 g/l, k-SFLC 182 mg/l, k/l-ratio 60.5. BM biopsy revealed 40% PC infiltration. Cytogenetics were favorable (trisomy 5p15, 9q22, 11q13 und 15q22). The ISS and R-ISS were both I, Durie & Salmon stage was IIIA and symptomatic MM was diagnosed with 1/4 CRAB symptoms. The patient was classified as fit for ASCT (R-MCI-score: 2/9 = fit) [7–9]. We included the patient into the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Induction with elotuzumab, CFZ, lenalidomide and dexamethasone (E-KRd, 6 cycles) and ASCT with melphalan 200 mg/m2 were performed and due to repeated respiratory infections (boca- and corona (CoV NL 63) virus) dose reductions of elotuzumab and lenalidomide were executed. Before ASCT, kappa-SFLC decreased to 12.8 mg/l (vgPR).
In 01/20, within the last (4th) cycle of E-KRd consolidation, the patient developed fever and acute kidney failure with creatinine 1.7 mg/dl (GFR 40 ml/min, MRDRD; baseline-creatinine: 1 mg/dl). Prerenal genesis was assumed (fractional sodium excretion < 1%) and fluids were infused. However, creatinine elevation did not resolve finally reaching acute kidney injury stage 3 according to AKIN and proteinuria reached 6.2 g/d. The patient developed headache and high blood pressure (BP 220/105 mmHg). Platelets and Hb gradually decreased (Fig. 1b), haptoglobin was < 5 mg/dl. In the peripheral blood smear, 44‰ schistocytes were visible; ADAMTS13 activity and antigen were normal (58% and 0.40 IU/ml, respectively) and Coombs test negative. Blood culture additionally showed Staphylococcus epidermidis due to port infection and throat swab detected influenza A (H3N2) and B.
Since TMA was diagnosed (LDH/platelets ratio 88.3), high-dose glucocorticoids and TPE were applied (before completion of diagnostics). Without substantial improvement, five days after first plasmapheresis our patient received eculizumab (Fig. 1b), starting at 900 mg. A total of 11 sessions of plasma exchange at a daily basis were performed with FFP as replacement (Fig. 1b). Parameters of hemolysis rapidly improved, so that glucocorticoids could be expeditiously reduced and eculizumab was terminated after four cycles with 900 mg/weekly and two doses with 1200 mg/every two weeks (Fig. 1b).
In 05/19, the patient showed VGPR of his MM, the BMPC infiltration even CR (polyclonal PCs of 5%) and gradual renal function improvement (eGFR improved from 10 to 32 ml/min). Maintenance therapy with reduced doses of elotuzumab-lenalidomide (E-R: lenalidomide with 5 mg d1-28) was successfully initiated and TMA has remained in CR.
Discussion and conclusion
Hemolysis is a rather rare cause for anemia in MM [12]. When anemia is accompanied with thrombocytopenia, acute kidney injury, high blood pressure, neurological or unexplained extrarenal symptoms TMA should be considered. TMA includes a group of etiologically diverse diseases: Primary TMA, which include atypical HUS (aHUS) or thrombotic thrombocytopenic purpura (TTP) and secondary TMA and infection-associated TMA, involving Shiga-toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) [6, 13, 14]. TTP, in contrast to other TMA forms, is defined by decreased activity of the vWF-cleaving enzyme ADAMTS13 [6]. Unlike “typical” HUS, which is triggered by infections with STEC, complement mediated TMA is driven by uncontrolled complement activation and affected patients frequently harbor mutations in complement regulatory proteins (Fig. 2b) [15]. Secondary TMA is elicited by medication, malignancy, pregnancy, malignant hypertension, transplantations, infections or associated to autoimmune diseases [6, 10, 12–14]. As reviewed recently [6], TMA in MM can be elicited by ASCT- or allogeneic-SCT, MM progression, or anti-myeloma therapy. Drug-induced TMA (DITMA) may occur in MM due to PIs bortezomib or CFZ [3, 16, 17]. CFZ-TMA can appear early after onset of the drug, but also as late as two years after first administration [1, 2]. CFZ-TMA is probably driven by complement activation of the alternative pathway in terms of complement-mediated TMA [2–4, 18]. Blasco et al. described three cases in which plasma samples from patients with CFZ-TMA, led to depositions of complex membrane attack complex (C5b-9) of on endothelial cells, suggesting a complement overactivation [4]. Supporting this assumption, proteasome inhibition has been found to block Factor H, consequently leading to complement activation (Fig. 2b) [11]. Bortezomib-induced cases of TMA are attributed to decreased activity of ADAMTS13 [19, 20]. However, the majority of bortezomib-induced cases of TMA/TTP had only slightly decreased ADAMTS13 activity and PI-induced TMA in MM might be generally based on pathological overactivation of the alternative complement pathway rather than TTP [6]. In patient #2, TMA was either induced by CFZ or influenza A or B [15, 21]. Also a combination of both preexistent vascular endothelial injury due to CFZ and transient complement activation during influenza infection was eagerly discussed within our group. In this respect, eculizumab could be effective in patients treated with concurrent PI treatment, infection and TMA.
In patient #2, in contrast to patient #1, C3 and C4 levels were normal; CH50 and C5b-9, the terminal pathway of the complement pathway were, however, not assessed. The fast response to eculizumab and the lacking effect of TPE seemed to argue for pathological complement activation, but it cannot be ruled out that the classical or the alternative complement pathway was involved. Importantly, both patients developed TMA several weeks after ASCT. Since TA-TMA was described to occur in a complement-dependent manner, like complement mediated TMA [10], a combination of TMA-triggers is likewise conceivable.
Taken together, several factors might have induced TMA in our patients: ASCT, genetic predispositions, viral infections and the underlying CFZ treatment. Thus, definite causality could ot be entirely proven. The major criticism of our study may be missing additional in vitro studies of complement activation and the unavailability of renal biopsies for further diagnostics. Kidney biopsies had been discussed interdisciplinary in our weekly MM tumor board, however, in the acute clinical setting, the potential biopsy risk, especially bleeding, was judged to outweigh potential benefits and on top, both patients had declined kidney biopsies.
In respect to therapy for TMA in MM, definitive clinical practical guidelines do not exist [6]. For DITMA, the causative drug must be discontinued promptly, high-dose glucocorticoids are given and plasmapheresis is performed [2, 6]. In CFZ-TMA, successful treatment with eculizumab, a terminal complement pathway inhibitor, was described in six cases to our knowledge [1, 2, 4, 5, 22]. Nevertheless, reports of TMA in MM remain scarce, and the definitive treatment regimen as well as definitive duration of treatment are unclear [6]: Portuguese and Lipe (2018), Moliz et al. (2019) and Blasco et al. (2020) administered eculizumab for up to three weekly doses [2, 4, 22], whereas Bhutani et al. (2020) for four months [1]. In our two cases, only after eculizumab initiation, hemolysis and creatinine levels improved impressively (Fig. 1A,B), plus the application period of two months of eculizumab was efficient without relapsing TMA, thus appears possible to be shorter than four months. On the other hand a shorter treatment period, as reported by Portuguese and Lipe, might be insufficient as one of their eculizumab-treated patients stayed on hemodialysis with this regime [22].
TPE is generally recommended for TMA. Plasma exchange, however, is not without side effects, and can remove therapeutic antibodies from the circulation, thus its concurrent use is not recommended [6, 10]. Interestingly, in our cases the success of eculizumab was not fully dependent on the termination of TPE, since in patient #2 TPE was continued during the first two eculizumab doses. In this respect, concerns, that TPE would remove eculizumab from the blood or restore C5-levels available for activation, seem unfounded. On the other hand, a significant improvement of creatinine-levels and platelets was only achieved after termination of TPE in patient #2 (Fig. 1B). Thus, irrespective of the cause of TMA in MM patients under PI treatment or shortly after ASCT, eculizumab rather than TPE could be considered as standard first-line therapy [2, 6] (Fig. 3). Increased susceptibility to meningococcal infection during eculizumab treatment has to be considered and vaccination should be implemented [23]. As soon as ADAMTS13 activity is proven to be within the normal range (50–150%) and TTP is excluded, further treatment decisions can be drawn [6]. Additionally, in our experience short-term use of eculizumab was sufficient for effective TMA treatment. Furthermore, eculizumab treatment did not worsen MM parameters in neither of our patients.
Fig. 3 Guideline for diagnostic and therapeutic approach for TMA in MM: Whenever clinical and laboratory findings are consistent with TMA, one should rapidly terminate possible causative drugs, initiate therapeutic plasma exchange (TPE) and apply a first dose of eculizumab. As soon as ADAMTS13 activity is determined further therapeutic decisions can be drawn
Taken together, CFZ-induced TMA is a serious event and should be assumed in treated MM patients with rapid acute kidney failure and hemolysis. Fast treatment initiation with eculizumab can reverse pathological complement system activation and prevent organ damage. As shown in our patients, early initiated, short-term treatment with eculizumab can sufficiently terminate CFZ-TMA and counteract TMA-poor prognostic factors.
Abbreviations
aHUSAtypical hemolytic uremic syndrome
AKINAcute kidney injury network
ASCTAutologous stem cell transplantation
BMBone marrow
CFZ-TMACarfilzomib-induced thrombotic microangiopathy
CRComplete response
DITMADrug-induced thrombotic microangiopathy
FFPFresh frozen plasma
TMAThrombotic microangiopathy
TPETherapeutic plasma exchange
TTPThrombotic thrombocytopenic purpura
MMMultiple myeloma
PCPlasma cell
PIProteasome inhibitor
STECShiga-toxin-producing E.coli
vgPRVery good partial response
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Michael Rassner, Rebecca Baur, Andreas Mackensen and Monika Engelhardt contributed equally to this work.
Acknowledgements
We would like to thank both patients for consent of publication of their educational cases within this work.
Authors’ contributions
MR and RB treated the patients, drafted and wrote the manuscript; JS, MS and RW treated the patient and revised the manuscript; AM and ME treated the patient, initiated and wrote the manuscript. All authors read and approved the final manuscript.
Funding
There was no funding received to support this research. Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
We have obtained written consent for publication from both patients presented in this case report.
Competing interests
The authors declare that they have no competing interests. | CARFILZOMIB, DEXAMETHASONE, ELOTUZUMAB, LENALIDOMIDE | DrugsGivenReaction | CC BY | 33461512 | 18,819,690 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Influenza B virus test positive'. | Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma.
Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.
The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.
In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.
Background
Thrombotic microangiopathy (TMA) is a rare cause of anemia in multiple myeloma (MM) patients, but can occasionally be elicited by common anti-myeloma drugs, especially by proteasome-inhibitors (PI) like carfilzomib (CFZ) [1–3]. Reports about TMA in MM induced by CFZ and optimal therapeutic approaches are scarce. Recently, single case reports described successful treatment of TMA in MM with the terminal complement pathway inhibitor eculizumab [1, 2, 4–6]. Definitive treatment recommendations, however, are lacking. Below we describe two cases of CFZ-induced TMA, that were successfully treated by eculizumab and provide evidence about precise therapeutic work-flow and possible interventions.
Case 1
A 43-year old male patient was diagnosed with IgG-kappa-MM in August 2018. At admission, we found extensive osteolysis and an acute kidney failure with a serum-creatinine of 4.2 mg/dl [0.67–1.17] (GFR 15 ml/min; MDRD) without previous history of impaired kidney function. With highly elevated serum free kappa light chains (kappa-SFLC) 3645 mg/l [0.35–15.10] and 4.2 g/d [< 0.15] urinary protein excretion, in the absence of albuminuria, cast nephropathy was assumed as the most likely cause of acute kidney failure. Since there was no sign of further organ injury, amyloidosis seemed unlikely, as well MIDD (monoclonal immunoglobulin deposition disease), which is often accompanied by amyloidosis and presents with albuminuria. The type of renal injury was not further determined by kidney puncture. The M-protein was elevated with 37 g/l, IgG 52.3 g/l [6.1-16.16], k/l-ratio 864 [0.46-4], hemoglobin (Hb) 9.5 g/dl [13.5–17.5], β2-microglobulin 8.7 mg/dl [0-2.34], serum calcium and LDH were normal. The bone marrow plasma cell (BMPC) infiltration was 15%, FISH excluded high-risk cytogenetics. Following the ISS grading system, we diagnosed an IgG-kappa-MM stage III (Durie & Salmon stage IIIB) and symptomatic myeloma with 3/4 CRAB criteria (anemia, renal impairment, bone lesions). The revised myeloma comorbidity index (R-MCI: 1/9 = fit/low-risk) revealed a fit patient [7–9]. Due to the CRAB-criteria, specifically renal impairment, chemotherapy was initiated with one cycle of bortezomib, doxorubicin, dexamethasone (BAD) followed by two cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) after improvement of the kidney function and resolved urinary proteinuria. Since M-protein reduction was insufficient (21.4 g/l), the regimen was switched a second time to CFZ, lenalidomide and dexamethasone (KRd). After two cycles KRd, a partial remission (PR; M-protein 5.3 g/l, IgG 6.4 g/l) was achieved and high-dose melphalan (200 mg/m²) chemotherapy with autologous stem cell transplantation (ASCT) was performed. On day (d) 42 post ASCT IgG levels were increasing again (21.1 g/l). Based on the distinct improvement of the myeloma markers after KRd and a missing additional response to ASCT, our MM-tumor board decided to apply three consolidation cycles of KRd. In May 2019, the 3rd KRd cycle (1st consolidation cycle after ASCT) was initiated. At d2 of CFZ, the patient developed fever, dyspnea and malaise. Platelets were 11Tsd/µl, Hb 10.8 g/dl, LDH 1836U/l, haptoglobin < 150 mg/l, unconjugated bilirubin 2.7 mg/dl, the creatinine rose from 0.72 to 2.07 mg/dl [0.67–1.17] (GFR > 60 to 35 ml/min) (Fig. 1a) and urinary proteinuria increased from normal values to 52 g/l [< 0.135]. In the peripheral blood smear, 11‰ schistocytes were detected and an altered complement profile with reduced C3 and C4 levels was found (C3 77.6md/dl, C4 9.9 mg/dl). TMA-Index (LDH/platelets ratio) was elevated to 166. These findings (schistocytes > 10‰, elevated creatinine and TMA-Index) have been described as poor prognostic factors for transplant associated-TMA (TA-TMA) [10]. Of note, two days earlier, lab results had been normal (Fig. 1a). Chest CT scan showed bilateral infiltrates, matching pulmonary hemorrhage (Fig. 2). Due to the acute development of hemolysis, together with acute kidney injury, unsuspicious ATAMTS13 activity (61%) [50–110], normal ADAMTS13 antigen (0.48 IU/ml) [0.35–1.2] and direct Coombs test being negative, we suspected medication-induced TMA. Therapeutic plasma exchange (TPE) was initiated by replacement with fresh frozen plasma (FFP) on a daily regimen and on account of declining kidney function with development of acute kidney injury stage 3 according to the acute Kidney Injury Network (AKIN), dialysis was necessary one day later. After six days of TPE neither LDH nor platelets improved. Assuming CFZ-induced TMA, we administered eculizumab (900 mg) along with meningococcal vaccination and initiation of antibiotic prophylaxis. Five days later, LDH declined to 818U/l and platelet counts improved to 58Tsd/µl without transfusions. We continued eculizumab (900 mg) weekly. After the fourth application, dialysis could be discontinued. Platelet counts normalized within two months after treatment initiation of eculizumab and there were no further signs of TMA, thus eculizumab was terminated (Fig. 1a). One year after TMA diagnosis and KRd consolidation, our patient remains in PR of his MM and CR of the CFZ-induced TMA.
Fig. 1 Course of CFZ-TMA in the two patients. a Case #1: This patient developed acute kidney injury, fever and pulmonary hemorrhage during the first consolidation with carfilzomib, lenalidomide and dexamethasone (KRd) after ASCT. Laboratory findings (thrombocytopenia) and schistocytosis of 11‰ were consistent with thrombotic microangiopathy (TMA). Therapeutic plasma exchange (TPE) was immediately initiated, but shortly after dialysis was necessary. As blood values did not improve, we finally administered eculizumab for a total of seven doses and saw a rapid response in LDH, platelet number and kidney function with our patient being still in PR. b Case #2: This patient, who is treated in the DSMM XVII study (Arm A: Elotuzumab-KRd) developed head ache, malignant hypertension and laboratory distortions (thrombocytopenia, increase of LDH and acute kidney injury) consistent with TMA. After a short period of TPE, eculizumab was infused (total of six infusions). Blood values improved but kidney function remains decreased
Fig. 2 a Chest-CT in patient case 1, d1 of CFZ-TMA onset: Bipulmonary extensive ground-glass opacities in all lung fields, mostly omitting the periphery and predominantly occurring in the right lung. b Mechanism of CFZ-TMA: Within the proximal complement activation C3 is cleaved by the C3 convertase to anaphylactic 3a and C3b. C3b then cleaves C5 to C5a and C5b, the latter together with C6-C9 forming the membrane attack complex (MAC) within the terminal pathway. Activity of the C3 convertase is regulated by complement factor H and regulated proteins. Proteasome inhibition blocks CFH [11]. The monoclonal antibody eculizumab counteracts the resulting overactivation of C3b by binding C5
Case 2
The second 59-year-old male patient was diagnosed with IgG-kappa-MM in 11/2018. CT scan revealed osteolysis of the sacrum, pelvis and vertebrae. Calcium and creatinine were normal and the Hb was slightly decreased (13.3 g/dl). IgG was 38.4 g/l, k-SFLC 182 mg/l, k/l-ratio 60.5. BM biopsy revealed 40% PC infiltration. Cytogenetics were favorable (trisomy 5p15, 9q22, 11q13 und 15q22). The ISS and R-ISS were both I, Durie & Salmon stage was IIIA and symptomatic MM was diagnosed with 1/4 CRAB symptoms. The patient was classified as fit for ASCT (R-MCI-score: 2/9 = fit) [7–9]. We included the patient into the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Induction with elotuzumab, CFZ, lenalidomide and dexamethasone (E-KRd, 6 cycles) and ASCT with melphalan 200 mg/m2 were performed and due to repeated respiratory infections (boca- and corona (CoV NL 63) virus) dose reductions of elotuzumab and lenalidomide were executed. Before ASCT, kappa-SFLC decreased to 12.8 mg/l (vgPR).
In 01/20, within the last (4th) cycle of E-KRd consolidation, the patient developed fever and acute kidney failure with creatinine 1.7 mg/dl (GFR 40 ml/min, MRDRD; baseline-creatinine: 1 mg/dl). Prerenal genesis was assumed (fractional sodium excretion < 1%) and fluids were infused. However, creatinine elevation did not resolve finally reaching acute kidney injury stage 3 according to AKIN and proteinuria reached 6.2 g/d. The patient developed headache and high blood pressure (BP 220/105 mmHg). Platelets and Hb gradually decreased (Fig. 1b), haptoglobin was < 5 mg/dl. In the peripheral blood smear, 44‰ schistocytes were visible; ADAMTS13 activity and antigen were normal (58% and 0.40 IU/ml, respectively) and Coombs test negative. Blood culture additionally showed Staphylococcus epidermidis due to port infection and throat swab detected influenza A (H3N2) and B.
Since TMA was diagnosed (LDH/platelets ratio 88.3), high-dose glucocorticoids and TPE were applied (before completion of diagnostics). Without substantial improvement, five days after first plasmapheresis our patient received eculizumab (Fig. 1b), starting at 900 mg. A total of 11 sessions of plasma exchange at a daily basis were performed with FFP as replacement (Fig. 1b). Parameters of hemolysis rapidly improved, so that glucocorticoids could be expeditiously reduced and eculizumab was terminated after four cycles with 900 mg/weekly and two doses with 1200 mg/every two weeks (Fig. 1b).
In 05/19, the patient showed VGPR of his MM, the BMPC infiltration even CR (polyclonal PCs of 5%) and gradual renal function improvement (eGFR improved from 10 to 32 ml/min). Maintenance therapy with reduced doses of elotuzumab-lenalidomide (E-R: lenalidomide with 5 mg d1-28) was successfully initiated and TMA has remained in CR.
Discussion and conclusion
Hemolysis is a rather rare cause for anemia in MM [12]. When anemia is accompanied with thrombocytopenia, acute kidney injury, high blood pressure, neurological or unexplained extrarenal symptoms TMA should be considered. TMA includes a group of etiologically diverse diseases: Primary TMA, which include atypical HUS (aHUS) or thrombotic thrombocytopenic purpura (TTP) and secondary TMA and infection-associated TMA, involving Shiga-toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) [6, 13, 14]. TTP, in contrast to other TMA forms, is defined by decreased activity of the vWF-cleaving enzyme ADAMTS13 [6]. Unlike “typical” HUS, which is triggered by infections with STEC, complement mediated TMA is driven by uncontrolled complement activation and affected patients frequently harbor mutations in complement regulatory proteins (Fig. 2b) [15]. Secondary TMA is elicited by medication, malignancy, pregnancy, malignant hypertension, transplantations, infections or associated to autoimmune diseases [6, 10, 12–14]. As reviewed recently [6], TMA in MM can be elicited by ASCT- or allogeneic-SCT, MM progression, or anti-myeloma therapy. Drug-induced TMA (DITMA) may occur in MM due to PIs bortezomib or CFZ [3, 16, 17]. CFZ-TMA can appear early after onset of the drug, but also as late as two years after first administration [1, 2]. CFZ-TMA is probably driven by complement activation of the alternative pathway in terms of complement-mediated TMA [2–4, 18]. Blasco et al. described three cases in which plasma samples from patients with CFZ-TMA, led to depositions of complex membrane attack complex (C5b-9) of on endothelial cells, suggesting a complement overactivation [4]. Supporting this assumption, proteasome inhibition has been found to block Factor H, consequently leading to complement activation (Fig. 2b) [11]. Bortezomib-induced cases of TMA are attributed to decreased activity of ADAMTS13 [19, 20]. However, the majority of bortezomib-induced cases of TMA/TTP had only slightly decreased ADAMTS13 activity and PI-induced TMA in MM might be generally based on pathological overactivation of the alternative complement pathway rather than TTP [6]. In patient #2, TMA was either induced by CFZ or influenza A or B [15, 21]. Also a combination of both preexistent vascular endothelial injury due to CFZ and transient complement activation during influenza infection was eagerly discussed within our group. In this respect, eculizumab could be effective in patients treated with concurrent PI treatment, infection and TMA.
In patient #2, in contrast to patient #1, C3 and C4 levels were normal; CH50 and C5b-9, the terminal pathway of the complement pathway were, however, not assessed. The fast response to eculizumab and the lacking effect of TPE seemed to argue for pathological complement activation, but it cannot be ruled out that the classical or the alternative complement pathway was involved. Importantly, both patients developed TMA several weeks after ASCT. Since TA-TMA was described to occur in a complement-dependent manner, like complement mediated TMA [10], a combination of TMA-triggers is likewise conceivable.
Taken together, several factors might have induced TMA in our patients: ASCT, genetic predispositions, viral infections and the underlying CFZ treatment. Thus, definite causality could ot be entirely proven. The major criticism of our study may be missing additional in vitro studies of complement activation and the unavailability of renal biopsies for further diagnostics. Kidney biopsies had been discussed interdisciplinary in our weekly MM tumor board, however, in the acute clinical setting, the potential biopsy risk, especially bleeding, was judged to outweigh potential benefits and on top, both patients had declined kidney biopsies.
In respect to therapy for TMA in MM, definitive clinical practical guidelines do not exist [6]. For DITMA, the causative drug must be discontinued promptly, high-dose glucocorticoids are given and plasmapheresis is performed [2, 6]. In CFZ-TMA, successful treatment with eculizumab, a terminal complement pathway inhibitor, was described in six cases to our knowledge [1, 2, 4, 5, 22]. Nevertheless, reports of TMA in MM remain scarce, and the definitive treatment regimen as well as definitive duration of treatment are unclear [6]: Portuguese and Lipe (2018), Moliz et al. (2019) and Blasco et al. (2020) administered eculizumab for up to three weekly doses [2, 4, 22], whereas Bhutani et al. (2020) for four months [1]. In our two cases, only after eculizumab initiation, hemolysis and creatinine levels improved impressively (Fig. 1A,B), plus the application period of two months of eculizumab was efficient without relapsing TMA, thus appears possible to be shorter than four months. On the other hand a shorter treatment period, as reported by Portuguese and Lipe, might be insufficient as one of their eculizumab-treated patients stayed on hemodialysis with this regime [22].
TPE is generally recommended for TMA. Plasma exchange, however, is not without side effects, and can remove therapeutic antibodies from the circulation, thus its concurrent use is not recommended [6, 10]. Interestingly, in our cases the success of eculizumab was not fully dependent on the termination of TPE, since in patient #2 TPE was continued during the first two eculizumab doses. In this respect, concerns, that TPE would remove eculizumab from the blood or restore C5-levels available for activation, seem unfounded. On the other hand, a significant improvement of creatinine-levels and platelets was only achieved after termination of TPE in patient #2 (Fig. 1B). Thus, irrespective of the cause of TMA in MM patients under PI treatment or shortly after ASCT, eculizumab rather than TPE could be considered as standard first-line therapy [2, 6] (Fig. 3). Increased susceptibility to meningococcal infection during eculizumab treatment has to be considered and vaccination should be implemented [23]. As soon as ADAMTS13 activity is proven to be within the normal range (50–150%) and TTP is excluded, further treatment decisions can be drawn [6]. Additionally, in our experience short-term use of eculizumab was sufficient for effective TMA treatment. Furthermore, eculizumab treatment did not worsen MM parameters in neither of our patients.
Fig. 3 Guideline for diagnostic and therapeutic approach for TMA in MM: Whenever clinical and laboratory findings are consistent with TMA, one should rapidly terminate possible causative drugs, initiate therapeutic plasma exchange (TPE) and apply a first dose of eculizumab. As soon as ADAMTS13 activity is determined further therapeutic decisions can be drawn
Taken together, CFZ-induced TMA is a serious event and should be assumed in treated MM patients with rapid acute kidney failure and hemolysis. Fast treatment initiation with eculizumab can reverse pathological complement system activation and prevent organ damage. As shown in our patients, early initiated, short-term treatment with eculizumab can sufficiently terminate CFZ-TMA and counteract TMA-poor prognostic factors.
Abbreviations
aHUSAtypical hemolytic uremic syndrome
AKINAcute kidney injury network
ASCTAutologous stem cell transplantation
BMBone marrow
CFZ-TMACarfilzomib-induced thrombotic microangiopathy
CRComplete response
DITMADrug-induced thrombotic microangiopathy
FFPFresh frozen plasma
TMAThrombotic microangiopathy
TPETherapeutic plasma exchange
TTPThrombotic thrombocytopenic purpura
MMMultiple myeloma
PCPlasma cell
PIProteasome inhibitor
STECShiga-toxin-producing E.coli
vgPRVery good partial response
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Michael Rassner, Rebecca Baur, Andreas Mackensen and Monika Engelhardt contributed equally to this work.
Acknowledgements
We would like to thank both patients for consent of publication of their educational cases within this work.
Authors’ contributions
MR and RB treated the patients, drafted and wrote the manuscript; JS, MS and RW treated the patient and revised the manuscript; AM and ME treated the patient, initiated and wrote the manuscript. All authors read and approved the final manuscript.
Funding
There was no funding received to support this research. Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
We have obtained written consent for publication from both patients presented in this case report.
Competing interests
The authors declare that they have no competing interests. | CARFILZOMIB, DEXAMETHASONE, ELOTUZUMAB, LENALIDOMIDE | DrugsGivenReaction | CC BY | 33461512 | 18,819,690 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory tract infection viral'. | Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma.
Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.
The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.
In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.
Background
Thrombotic microangiopathy (TMA) is a rare cause of anemia in multiple myeloma (MM) patients, but can occasionally be elicited by common anti-myeloma drugs, especially by proteasome-inhibitors (PI) like carfilzomib (CFZ) [1–3]. Reports about TMA in MM induced by CFZ and optimal therapeutic approaches are scarce. Recently, single case reports described successful treatment of TMA in MM with the terminal complement pathway inhibitor eculizumab [1, 2, 4–6]. Definitive treatment recommendations, however, are lacking. Below we describe two cases of CFZ-induced TMA, that were successfully treated by eculizumab and provide evidence about precise therapeutic work-flow and possible interventions.
Case 1
A 43-year old male patient was diagnosed with IgG-kappa-MM in August 2018. At admission, we found extensive osteolysis and an acute kidney failure with a serum-creatinine of 4.2 mg/dl [0.67–1.17] (GFR 15 ml/min; MDRD) without previous history of impaired kidney function. With highly elevated serum free kappa light chains (kappa-SFLC) 3645 mg/l [0.35–15.10] and 4.2 g/d [< 0.15] urinary protein excretion, in the absence of albuminuria, cast nephropathy was assumed as the most likely cause of acute kidney failure. Since there was no sign of further organ injury, amyloidosis seemed unlikely, as well MIDD (monoclonal immunoglobulin deposition disease), which is often accompanied by amyloidosis and presents with albuminuria. The type of renal injury was not further determined by kidney puncture. The M-protein was elevated with 37 g/l, IgG 52.3 g/l [6.1-16.16], k/l-ratio 864 [0.46-4], hemoglobin (Hb) 9.5 g/dl [13.5–17.5], β2-microglobulin 8.7 mg/dl [0-2.34], serum calcium and LDH were normal. The bone marrow plasma cell (BMPC) infiltration was 15%, FISH excluded high-risk cytogenetics. Following the ISS grading system, we diagnosed an IgG-kappa-MM stage III (Durie & Salmon stage IIIB) and symptomatic myeloma with 3/4 CRAB criteria (anemia, renal impairment, bone lesions). The revised myeloma comorbidity index (R-MCI: 1/9 = fit/low-risk) revealed a fit patient [7–9]. Due to the CRAB-criteria, specifically renal impairment, chemotherapy was initiated with one cycle of bortezomib, doxorubicin, dexamethasone (BAD) followed by two cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) after improvement of the kidney function and resolved urinary proteinuria. Since M-protein reduction was insufficient (21.4 g/l), the regimen was switched a second time to CFZ, lenalidomide and dexamethasone (KRd). After two cycles KRd, a partial remission (PR; M-protein 5.3 g/l, IgG 6.4 g/l) was achieved and high-dose melphalan (200 mg/m²) chemotherapy with autologous stem cell transplantation (ASCT) was performed. On day (d) 42 post ASCT IgG levels were increasing again (21.1 g/l). Based on the distinct improvement of the myeloma markers after KRd and a missing additional response to ASCT, our MM-tumor board decided to apply three consolidation cycles of KRd. In May 2019, the 3rd KRd cycle (1st consolidation cycle after ASCT) was initiated. At d2 of CFZ, the patient developed fever, dyspnea and malaise. Platelets were 11Tsd/µl, Hb 10.8 g/dl, LDH 1836U/l, haptoglobin < 150 mg/l, unconjugated bilirubin 2.7 mg/dl, the creatinine rose from 0.72 to 2.07 mg/dl [0.67–1.17] (GFR > 60 to 35 ml/min) (Fig. 1a) and urinary proteinuria increased from normal values to 52 g/l [< 0.135]. In the peripheral blood smear, 11‰ schistocytes were detected and an altered complement profile with reduced C3 and C4 levels was found (C3 77.6md/dl, C4 9.9 mg/dl). TMA-Index (LDH/platelets ratio) was elevated to 166. These findings (schistocytes > 10‰, elevated creatinine and TMA-Index) have been described as poor prognostic factors for transplant associated-TMA (TA-TMA) [10]. Of note, two days earlier, lab results had been normal (Fig. 1a). Chest CT scan showed bilateral infiltrates, matching pulmonary hemorrhage (Fig. 2). Due to the acute development of hemolysis, together with acute kidney injury, unsuspicious ATAMTS13 activity (61%) [50–110], normal ADAMTS13 antigen (0.48 IU/ml) [0.35–1.2] and direct Coombs test being negative, we suspected medication-induced TMA. Therapeutic plasma exchange (TPE) was initiated by replacement with fresh frozen plasma (FFP) on a daily regimen and on account of declining kidney function with development of acute kidney injury stage 3 according to the acute Kidney Injury Network (AKIN), dialysis was necessary one day later. After six days of TPE neither LDH nor platelets improved. Assuming CFZ-induced TMA, we administered eculizumab (900 mg) along with meningococcal vaccination and initiation of antibiotic prophylaxis. Five days later, LDH declined to 818U/l and platelet counts improved to 58Tsd/µl without transfusions. We continued eculizumab (900 mg) weekly. After the fourth application, dialysis could be discontinued. Platelet counts normalized within two months after treatment initiation of eculizumab and there were no further signs of TMA, thus eculizumab was terminated (Fig. 1a). One year after TMA diagnosis and KRd consolidation, our patient remains in PR of his MM and CR of the CFZ-induced TMA.
Fig. 1 Course of CFZ-TMA in the two patients. a Case #1: This patient developed acute kidney injury, fever and pulmonary hemorrhage during the first consolidation with carfilzomib, lenalidomide and dexamethasone (KRd) after ASCT. Laboratory findings (thrombocytopenia) and schistocytosis of 11‰ were consistent with thrombotic microangiopathy (TMA). Therapeutic plasma exchange (TPE) was immediately initiated, but shortly after dialysis was necessary. As blood values did not improve, we finally administered eculizumab for a total of seven doses and saw a rapid response in LDH, platelet number and kidney function with our patient being still in PR. b Case #2: This patient, who is treated in the DSMM XVII study (Arm A: Elotuzumab-KRd) developed head ache, malignant hypertension and laboratory distortions (thrombocytopenia, increase of LDH and acute kidney injury) consistent with TMA. After a short period of TPE, eculizumab was infused (total of six infusions). Blood values improved but kidney function remains decreased
Fig. 2 a Chest-CT in patient case 1, d1 of CFZ-TMA onset: Bipulmonary extensive ground-glass opacities in all lung fields, mostly omitting the periphery and predominantly occurring in the right lung. b Mechanism of CFZ-TMA: Within the proximal complement activation C3 is cleaved by the C3 convertase to anaphylactic 3a and C3b. C3b then cleaves C5 to C5a and C5b, the latter together with C6-C9 forming the membrane attack complex (MAC) within the terminal pathway. Activity of the C3 convertase is regulated by complement factor H and regulated proteins. Proteasome inhibition blocks CFH [11]. The monoclonal antibody eculizumab counteracts the resulting overactivation of C3b by binding C5
Case 2
The second 59-year-old male patient was diagnosed with IgG-kappa-MM in 11/2018. CT scan revealed osteolysis of the sacrum, pelvis and vertebrae. Calcium and creatinine were normal and the Hb was slightly decreased (13.3 g/dl). IgG was 38.4 g/l, k-SFLC 182 mg/l, k/l-ratio 60.5. BM biopsy revealed 40% PC infiltration. Cytogenetics were favorable (trisomy 5p15, 9q22, 11q13 und 15q22). The ISS and R-ISS were both I, Durie & Salmon stage was IIIA and symptomatic MM was diagnosed with 1/4 CRAB symptoms. The patient was classified as fit for ASCT (R-MCI-score: 2/9 = fit) [7–9]. We included the patient into the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Induction with elotuzumab, CFZ, lenalidomide and dexamethasone (E-KRd, 6 cycles) and ASCT with melphalan 200 mg/m2 were performed and due to repeated respiratory infections (boca- and corona (CoV NL 63) virus) dose reductions of elotuzumab and lenalidomide were executed. Before ASCT, kappa-SFLC decreased to 12.8 mg/l (vgPR).
In 01/20, within the last (4th) cycle of E-KRd consolidation, the patient developed fever and acute kidney failure with creatinine 1.7 mg/dl (GFR 40 ml/min, MRDRD; baseline-creatinine: 1 mg/dl). Prerenal genesis was assumed (fractional sodium excretion < 1%) and fluids were infused. However, creatinine elevation did not resolve finally reaching acute kidney injury stage 3 according to AKIN and proteinuria reached 6.2 g/d. The patient developed headache and high blood pressure (BP 220/105 mmHg). Platelets and Hb gradually decreased (Fig. 1b), haptoglobin was < 5 mg/dl. In the peripheral blood smear, 44‰ schistocytes were visible; ADAMTS13 activity and antigen were normal (58% and 0.40 IU/ml, respectively) and Coombs test negative. Blood culture additionally showed Staphylococcus epidermidis due to port infection and throat swab detected influenza A (H3N2) and B.
Since TMA was diagnosed (LDH/platelets ratio 88.3), high-dose glucocorticoids and TPE were applied (before completion of diagnostics). Without substantial improvement, five days after first plasmapheresis our patient received eculizumab (Fig. 1b), starting at 900 mg. A total of 11 sessions of plasma exchange at a daily basis were performed with FFP as replacement (Fig. 1b). Parameters of hemolysis rapidly improved, so that glucocorticoids could be expeditiously reduced and eculizumab was terminated after four cycles with 900 mg/weekly and two doses with 1200 mg/every two weeks (Fig. 1b).
In 05/19, the patient showed VGPR of his MM, the BMPC infiltration even CR (polyclonal PCs of 5%) and gradual renal function improvement (eGFR improved from 10 to 32 ml/min). Maintenance therapy with reduced doses of elotuzumab-lenalidomide (E-R: lenalidomide with 5 mg d1-28) was successfully initiated and TMA has remained in CR.
Discussion and conclusion
Hemolysis is a rather rare cause for anemia in MM [12]. When anemia is accompanied with thrombocytopenia, acute kidney injury, high blood pressure, neurological or unexplained extrarenal symptoms TMA should be considered. TMA includes a group of etiologically diverse diseases: Primary TMA, which include atypical HUS (aHUS) or thrombotic thrombocytopenic purpura (TTP) and secondary TMA and infection-associated TMA, involving Shiga-toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) [6, 13, 14]. TTP, in contrast to other TMA forms, is defined by decreased activity of the vWF-cleaving enzyme ADAMTS13 [6]. Unlike “typical” HUS, which is triggered by infections with STEC, complement mediated TMA is driven by uncontrolled complement activation and affected patients frequently harbor mutations in complement regulatory proteins (Fig. 2b) [15]. Secondary TMA is elicited by medication, malignancy, pregnancy, malignant hypertension, transplantations, infections or associated to autoimmune diseases [6, 10, 12–14]. As reviewed recently [6], TMA in MM can be elicited by ASCT- or allogeneic-SCT, MM progression, or anti-myeloma therapy. Drug-induced TMA (DITMA) may occur in MM due to PIs bortezomib or CFZ [3, 16, 17]. CFZ-TMA can appear early after onset of the drug, but also as late as two years after first administration [1, 2]. CFZ-TMA is probably driven by complement activation of the alternative pathway in terms of complement-mediated TMA [2–4, 18]. Blasco et al. described three cases in which plasma samples from patients with CFZ-TMA, led to depositions of complex membrane attack complex (C5b-9) of on endothelial cells, suggesting a complement overactivation [4]. Supporting this assumption, proteasome inhibition has been found to block Factor H, consequently leading to complement activation (Fig. 2b) [11]. Bortezomib-induced cases of TMA are attributed to decreased activity of ADAMTS13 [19, 20]. However, the majority of bortezomib-induced cases of TMA/TTP had only slightly decreased ADAMTS13 activity and PI-induced TMA in MM might be generally based on pathological overactivation of the alternative complement pathway rather than TTP [6]. In patient #2, TMA was either induced by CFZ or influenza A or B [15, 21]. Also a combination of both preexistent vascular endothelial injury due to CFZ and transient complement activation during influenza infection was eagerly discussed within our group. In this respect, eculizumab could be effective in patients treated with concurrent PI treatment, infection and TMA.
In patient #2, in contrast to patient #1, C3 and C4 levels were normal; CH50 and C5b-9, the terminal pathway of the complement pathway were, however, not assessed. The fast response to eculizumab and the lacking effect of TPE seemed to argue for pathological complement activation, but it cannot be ruled out that the classical or the alternative complement pathway was involved. Importantly, both patients developed TMA several weeks after ASCT. Since TA-TMA was described to occur in a complement-dependent manner, like complement mediated TMA [10], a combination of TMA-triggers is likewise conceivable.
Taken together, several factors might have induced TMA in our patients: ASCT, genetic predispositions, viral infections and the underlying CFZ treatment. Thus, definite causality could ot be entirely proven. The major criticism of our study may be missing additional in vitro studies of complement activation and the unavailability of renal biopsies for further diagnostics. Kidney biopsies had been discussed interdisciplinary in our weekly MM tumor board, however, in the acute clinical setting, the potential biopsy risk, especially bleeding, was judged to outweigh potential benefits and on top, both patients had declined kidney biopsies.
In respect to therapy for TMA in MM, definitive clinical practical guidelines do not exist [6]. For DITMA, the causative drug must be discontinued promptly, high-dose glucocorticoids are given and plasmapheresis is performed [2, 6]. In CFZ-TMA, successful treatment with eculizumab, a terminal complement pathway inhibitor, was described in six cases to our knowledge [1, 2, 4, 5, 22]. Nevertheless, reports of TMA in MM remain scarce, and the definitive treatment regimen as well as definitive duration of treatment are unclear [6]: Portuguese and Lipe (2018), Moliz et al. (2019) and Blasco et al. (2020) administered eculizumab for up to three weekly doses [2, 4, 22], whereas Bhutani et al. (2020) for four months [1]. In our two cases, only after eculizumab initiation, hemolysis and creatinine levels improved impressively (Fig. 1A,B), plus the application period of two months of eculizumab was efficient without relapsing TMA, thus appears possible to be shorter than four months. On the other hand a shorter treatment period, as reported by Portuguese and Lipe, might be insufficient as one of their eculizumab-treated patients stayed on hemodialysis with this regime [22].
TPE is generally recommended for TMA. Plasma exchange, however, is not without side effects, and can remove therapeutic antibodies from the circulation, thus its concurrent use is not recommended [6, 10]. Interestingly, in our cases the success of eculizumab was not fully dependent on the termination of TPE, since in patient #2 TPE was continued during the first two eculizumab doses. In this respect, concerns, that TPE would remove eculizumab from the blood or restore C5-levels available for activation, seem unfounded. On the other hand, a significant improvement of creatinine-levels and platelets was only achieved after termination of TPE in patient #2 (Fig. 1B). Thus, irrespective of the cause of TMA in MM patients under PI treatment or shortly after ASCT, eculizumab rather than TPE could be considered as standard first-line therapy [2, 6] (Fig. 3). Increased susceptibility to meningococcal infection during eculizumab treatment has to be considered and vaccination should be implemented [23]. As soon as ADAMTS13 activity is proven to be within the normal range (50–150%) and TTP is excluded, further treatment decisions can be drawn [6]. Additionally, in our experience short-term use of eculizumab was sufficient for effective TMA treatment. Furthermore, eculizumab treatment did not worsen MM parameters in neither of our patients.
Fig. 3 Guideline for diagnostic and therapeutic approach for TMA in MM: Whenever clinical and laboratory findings are consistent with TMA, one should rapidly terminate possible causative drugs, initiate therapeutic plasma exchange (TPE) and apply a first dose of eculizumab. As soon as ADAMTS13 activity is determined further therapeutic decisions can be drawn
Taken together, CFZ-induced TMA is a serious event and should be assumed in treated MM patients with rapid acute kidney failure and hemolysis. Fast treatment initiation with eculizumab can reverse pathological complement system activation and prevent organ damage. As shown in our patients, early initiated, short-term treatment with eculizumab can sufficiently terminate CFZ-TMA and counteract TMA-poor prognostic factors.
Abbreviations
aHUSAtypical hemolytic uremic syndrome
AKINAcute kidney injury network
ASCTAutologous stem cell transplantation
BMBone marrow
CFZ-TMACarfilzomib-induced thrombotic microangiopathy
CRComplete response
DITMADrug-induced thrombotic microangiopathy
FFPFresh frozen plasma
TMAThrombotic microangiopathy
TPETherapeutic plasma exchange
TTPThrombotic thrombocytopenic purpura
MMMultiple myeloma
PCPlasma cell
PIProteasome inhibitor
STECShiga-toxin-producing E.coli
vgPRVery good partial response
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Michael Rassner, Rebecca Baur, Andreas Mackensen and Monika Engelhardt contributed equally to this work.
Acknowledgements
We would like to thank both patients for consent of publication of their educational cases within this work.
Authors’ contributions
MR and RB treated the patients, drafted and wrote the manuscript; JS, MS and RW treated the patient and revised the manuscript; AM and ME treated the patient, initiated and wrote the manuscript. All authors read and approved the final manuscript.
Funding
There was no funding received to support this research. Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
We have obtained written consent for publication from both patients presented in this case report.
Competing interests
The authors declare that they have no competing interests. | CARFILZOMIB, DEXAMETHASONE, ELOTUZUMAB, LENALIDOMIDE | DrugsGivenReaction | CC BY | 33461512 | 18,819,690 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Staphylococcus test positive'. | Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma.
Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.
The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.
In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.
Background
Thrombotic microangiopathy (TMA) is a rare cause of anemia in multiple myeloma (MM) patients, but can occasionally be elicited by common anti-myeloma drugs, especially by proteasome-inhibitors (PI) like carfilzomib (CFZ) [1–3]. Reports about TMA in MM induced by CFZ and optimal therapeutic approaches are scarce. Recently, single case reports described successful treatment of TMA in MM with the terminal complement pathway inhibitor eculizumab [1, 2, 4–6]. Definitive treatment recommendations, however, are lacking. Below we describe two cases of CFZ-induced TMA, that were successfully treated by eculizumab and provide evidence about precise therapeutic work-flow and possible interventions.
Case 1
A 43-year old male patient was diagnosed with IgG-kappa-MM in August 2018. At admission, we found extensive osteolysis and an acute kidney failure with a serum-creatinine of 4.2 mg/dl [0.67–1.17] (GFR 15 ml/min; MDRD) without previous history of impaired kidney function. With highly elevated serum free kappa light chains (kappa-SFLC) 3645 mg/l [0.35–15.10] and 4.2 g/d [< 0.15] urinary protein excretion, in the absence of albuminuria, cast nephropathy was assumed as the most likely cause of acute kidney failure. Since there was no sign of further organ injury, amyloidosis seemed unlikely, as well MIDD (monoclonal immunoglobulin deposition disease), which is often accompanied by amyloidosis and presents with albuminuria. The type of renal injury was not further determined by kidney puncture. The M-protein was elevated with 37 g/l, IgG 52.3 g/l [6.1-16.16], k/l-ratio 864 [0.46-4], hemoglobin (Hb) 9.5 g/dl [13.5–17.5], β2-microglobulin 8.7 mg/dl [0-2.34], serum calcium and LDH were normal. The bone marrow plasma cell (BMPC) infiltration was 15%, FISH excluded high-risk cytogenetics. Following the ISS grading system, we diagnosed an IgG-kappa-MM stage III (Durie & Salmon stage IIIB) and symptomatic myeloma with 3/4 CRAB criteria (anemia, renal impairment, bone lesions). The revised myeloma comorbidity index (R-MCI: 1/9 = fit/low-risk) revealed a fit patient [7–9]. Due to the CRAB-criteria, specifically renal impairment, chemotherapy was initiated with one cycle of bortezomib, doxorubicin, dexamethasone (BAD) followed by two cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) after improvement of the kidney function and resolved urinary proteinuria. Since M-protein reduction was insufficient (21.4 g/l), the regimen was switched a second time to CFZ, lenalidomide and dexamethasone (KRd). After two cycles KRd, a partial remission (PR; M-protein 5.3 g/l, IgG 6.4 g/l) was achieved and high-dose melphalan (200 mg/m²) chemotherapy with autologous stem cell transplantation (ASCT) was performed. On day (d) 42 post ASCT IgG levels were increasing again (21.1 g/l). Based on the distinct improvement of the myeloma markers after KRd and a missing additional response to ASCT, our MM-tumor board decided to apply three consolidation cycles of KRd. In May 2019, the 3rd KRd cycle (1st consolidation cycle after ASCT) was initiated. At d2 of CFZ, the patient developed fever, dyspnea and malaise. Platelets were 11Tsd/µl, Hb 10.8 g/dl, LDH 1836U/l, haptoglobin < 150 mg/l, unconjugated bilirubin 2.7 mg/dl, the creatinine rose from 0.72 to 2.07 mg/dl [0.67–1.17] (GFR > 60 to 35 ml/min) (Fig. 1a) and urinary proteinuria increased from normal values to 52 g/l [< 0.135]. In the peripheral blood smear, 11‰ schistocytes were detected and an altered complement profile with reduced C3 and C4 levels was found (C3 77.6md/dl, C4 9.9 mg/dl). TMA-Index (LDH/platelets ratio) was elevated to 166. These findings (schistocytes > 10‰, elevated creatinine and TMA-Index) have been described as poor prognostic factors for transplant associated-TMA (TA-TMA) [10]. Of note, two days earlier, lab results had been normal (Fig. 1a). Chest CT scan showed bilateral infiltrates, matching pulmonary hemorrhage (Fig. 2). Due to the acute development of hemolysis, together with acute kidney injury, unsuspicious ATAMTS13 activity (61%) [50–110], normal ADAMTS13 antigen (0.48 IU/ml) [0.35–1.2] and direct Coombs test being negative, we suspected medication-induced TMA. Therapeutic plasma exchange (TPE) was initiated by replacement with fresh frozen plasma (FFP) on a daily regimen and on account of declining kidney function with development of acute kidney injury stage 3 according to the acute Kidney Injury Network (AKIN), dialysis was necessary one day later. After six days of TPE neither LDH nor platelets improved. Assuming CFZ-induced TMA, we administered eculizumab (900 mg) along with meningococcal vaccination and initiation of antibiotic prophylaxis. Five days later, LDH declined to 818U/l and platelet counts improved to 58Tsd/µl without transfusions. We continued eculizumab (900 mg) weekly. After the fourth application, dialysis could be discontinued. Platelet counts normalized within two months after treatment initiation of eculizumab and there were no further signs of TMA, thus eculizumab was terminated (Fig. 1a). One year after TMA diagnosis and KRd consolidation, our patient remains in PR of his MM and CR of the CFZ-induced TMA.
Fig. 1 Course of CFZ-TMA in the two patients. a Case #1: This patient developed acute kidney injury, fever and pulmonary hemorrhage during the first consolidation with carfilzomib, lenalidomide and dexamethasone (KRd) after ASCT. Laboratory findings (thrombocytopenia) and schistocytosis of 11‰ were consistent with thrombotic microangiopathy (TMA). Therapeutic plasma exchange (TPE) was immediately initiated, but shortly after dialysis was necessary. As blood values did not improve, we finally administered eculizumab for a total of seven doses and saw a rapid response in LDH, platelet number and kidney function with our patient being still in PR. b Case #2: This patient, who is treated in the DSMM XVII study (Arm A: Elotuzumab-KRd) developed head ache, malignant hypertension and laboratory distortions (thrombocytopenia, increase of LDH and acute kidney injury) consistent with TMA. After a short period of TPE, eculizumab was infused (total of six infusions). Blood values improved but kidney function remains decreased
Fig. 2 a Chest-CT in patient case 1, d1 of CFZ-TMA onset: Bipulmonary extensive ground-glass opacities in all lung fields, mostly omitting the periphery and predominantly occurring in the right lung. b Mechanism of CFZ-TMA: Within the proximal complement activation C3 is cleaved by the C3 convertase to anaphylactic 3a and C3b. C3b then cleaves C5 to C5a and C5b, the latter together with C6-C9 forming the membrane attack complex (MAC) within the terminal pathway. Activity of the C3 convertase is regulated by complement factor H and regulated proteins. Proteasome inhibition blocks CFH [11]. The monoclonal antibody eculizumab counteracts the resulting overactivation of C3b by binding C5
Case 2
The second 59-year-old male patient was diagnosed with IgG-kappa-MM in 11/2018. CT scan revealed osteolysis of the sacrum, pelvis and vertebrae. Calcium and creatinine were normal and the Hb was slightly decreased (13.3 g/dl). IgG was 38.4 g/l, k-SFLC 182 mg/l, k/l-ratio 60.5. BM biopsy revealed 40% PC infiltration. Cytogenetics were favorable (trisomy 5p15, 9q22, 11q13 und 15q22). The ISS and R-ISS were both I, Durie & Salmon stage was IIIA and symptomatic MM was diagnosed with 1/4 CRAB symptoms. The patient was classified as fit for ASCT (R-MCI-score: 2/9 = fit) [7–9]. We included the patient into the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Induction with elotuzumab, CFZ, lenalidomide and dexamethasone (E-KRd, 6 cycles) and ASCT with melphalan 200 mg/m2 were performed and due to repeated respiratory infections (boca- and corona (CoV NL 63) virus) dose reductions of elotuzumab and lenalidomide were executed. Before ASCT, kappa-SFLC decreased to 12.8 mg/l (vgPR).
In 01/20, within the last (4th) cycle of E-KRd consolidation, the patient developed fever and acute kidney failure with creatinine 1.7 mg/dl (GFR 40 ml/min, MRDRD; baseline-creatinine: 1 mg/dl). Prerenal genesis was assumed (fractional sodium excretion < 1%) and fluids were infused. However, creatinine elevation did not resolve finally reaching acute kidney injury stage 3 according to AKIN and proteinuria reached 6.2 g/d. The patient developed headache and high blood pressure (BP 220/105 mmHg). Platelets and Hb gradually decreased (Fig. 1b), haptoglobin was < 5 mg/dl. In the peripheral blood smear, 44‰ schistocytes were visible; ADAMTS13 activity and antigen were normal (58% and 0.40 IU/ml, respectively) and Coombs test negative. Blood culture additionally showed Staphylococcus epidermidis due to port infection and throat swab detected influenza A (H3N2) and B.
Since TMA was diagnosed (LDH/platelets ratio 88.3), high-dose glucocorticoids and TPE were applied (before completion of diagnostics). Without substantial improvement, five days after first plasmapheresis our patient received eculizumab (Fig. 1b), starting at 900 mg. A total of 11 sessions of plasma exchange at a daily basis were performed with FFP as replacement (Fig. 1b). Parameters of hemolysis rapidly improved, so that glucocorticoids could be expeditiously reduced and eculizumab was terminated after four cycles with 900 mg/weekly and two doses with 1200 mg/every two weeks (Fig. 1b).
In 05/19, the patient showed VGPR of his MM, the BMPC infiltration even CR (polyclonal PCs of 5%) and gradual renal function improvement (eGFR improved from 10 to 32 ml/min). Maintenance therapy with reduced doses of elotuzumab-lenalidomide (E-R: lenalidomide with 5 mg d1-28) was successfully initiated and TMA has remained in CR.
Discussion and conclusion
Hemolysis is a rather rare cause for anemia in MM [12]. When anemia is accompanied with thrombocytopenia, acute kidney injury, high blood pressure, neurological or unexplained extrarenal symptoms TMA should be considered. TMA includes a group of etiologically diverse diseases: Primary TMA, which include atypical HUS (aHUS) or thrombotic thrombocytopenic purpura (TTP) and secondary TMA and infection-associated TMA, involving Shiga-toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) [6, 13, 14]. TTP, in contrast to other TMA forms, is defined by decreased activity of the vWF-cleaving enzyme ADAMTS13 [6]. Unlike “typical” HUS, which is triggered by infections with STEC, complement mediated TMA is driven by uncontrolled complement activation and affected patients frequently harbor mutations in complement regulatory proteins (Fig. 2b) [15]. Secondary TMA is elicited by medication, malignancy, pregnancy, malignant hypertension, transplantations, infections or associated to autoimmune diseases [6, 10, 12–14]. As reviewed recently [6], TMA in MM can be elicited by ASCT- or allogeneic-SCT, MM progression, or anti-myeloma therapy. Drug-induced TMA (DITMA) may occur in MM due to PIs bortezomib or CFZ [3, 16, 17]. CFZ-TMA can appear early after onset of the drug, but also as late as two years after first administration [1, 2]. CFZ-TMA is probably driven by complement activation of the alternative pathway in terms of complement-mediated TMA [2–4, 18]. Blasco et al. described three cases in which plasma samples from patients with CFZ-TMA, led to depositions of complex membrane attack complex (C5b-9) of on endothelial cells, suggesting a complement overactivation [4]. Supporting this assumption, proteasome inhibition has been found to block Factor H, consequently leading to complement activation (Fig. 2b) [11]. Bortezomib-induced cases of TMA are attributed to decreased activity of ADAMTS13 [19, 20]. However, the majority of bortezomib-induced cases of TMA/TTP had only slightly decreased ADAMTS13 activity and PI-induced TMA in MM might be generally based on pathological overactivation of the alternative complement pathway rather than TTP [6]. In patient #2, TMA was either induced by CFZ or influenza A or B [15, 21]. Also a combination of both preexistent vascular endothelial injury due to CFZ and transient complement activation during influenza infection was eagerly discussed within our group. In this respect, eculizumab could be effective in patients treated with concurrent PI treatment, infection and TMA.
In patient #2, in contrast to patient #1, C3 and C4 levels were normal; CH50 and C5b-9, the terminal pathway of the complement pathway were, however, not assessed. The fast response to eculizumab and the lacking effect of TPE seemed to argue for pathological complement activation, but it cannot be ruled out that the classical or the alternative complement pathway was involved. Importantly, both patients developed TMA several weeks after ASCT. Since TA-TMA was described to occur in a complement-dependent manner, like complement mediated TMA [10], a combination of TMA-triggers is likewise conceivable.
Taken together, several factors might have induced TMA in our patients: ASCT, genetic predispositions, viral infections and the underlying CFZ treatment. Thus, definite causality could ot be entirely proven. The major criticism of our study may be missing additional in vitro studies of complement activation and the unavailability of renal biopsies for further diagnostics. Kidney biopsies had been discussed interdisciplinary in our weekly MM tumor board, however, in the acute clinical setting, the potential biopsy risk, especially bleeding, was judged to outweigh potential benefits and on top, both patients had declined kidney biopsies.
In respect to therapy for TMA in MM, definitive clinical practical guidelines do not exist [6]. For DITMA, the causative drug must be discontinued promptly, high-dose glucocorticoids are given and plasmapheresis is performed [2, 6]. In CFZ-TMA, successful treatment with eculizumab, a terminal complement pathway inhibitor, was described in six cases to our knowledge [1, 2, 4, 5, 22]. Nevertheless, reports of TMA in MM remain scarce, and the definitive treatment regimen as well as definitive duration of treatment are unclear [6]: Portuguese and Lipe (2018), Moliz et al. (2019) and Blasco et al. (2020) administered eculizumab for up to three weekly doses [2, 4, 22], whereas Bhutani et al. (2020) for four months [1]. In our two cases, only after eculizumab initiation, hemolysis and creatinine levels improved impressively (Fig. 1A,B), plus the application period of two months of eculizumab was efficient without relapsing TMA, thus appears possible to be shorter than four months. On the other hand a shorter treatment period, as reported by Portuguese and Lipe, might be insufficient as one of their eculizumab-treated patients stayed on hemodialysis with this regime [22].
TPE is generally recommended for TMA. Plasma exchange, however, is not without side effects, and can remove therapeutic antibodies from the circulation, thus its concurrent use is not recommended [6, 10]. Interestingly, in our cases the success of eculizumab was not fully dependent on the termination of TPE, since in patient #2 TPE was continued during the first two eculizumab doses. In this respect, concerns, that TPE would remove eculizumab from the blood or restore C5-levels available for activation, seem unfounded. On the other hand, a significant improvement of creatinine-levels and platelets was only achieved after termination of TPE in patient #2 (Fig. 1B). Thus, irrespective of the cause of TMA in MM patients under PI treatment or shortly after ASCT, eculizumab rather than TPE could be considered as standard first-line therapy [2, 6] (Fig. 3). Increased susceptibility to meningococcal infection during eculizumab treatment has to be considered and vaccination should be implemented [23]. As soon as ADAMTS13 activity is proven to be within the normal range (50–150%) and TTP is excluded, further treatment decisions can be drawn [6]. Additionally, in our experience short-term use of eculizumab was sufficient for effective TMA treatment. Furthermore, eculizumab treatment did not worsen MM parameters in neither of our patients.
Fig. 3 Guideline for diagnostic and therapeutic approach for TMA in MM: Whenever clinical and laboratory findings are consistent with TMA, one should rapidly terminate possible causative drugs, initiate therapeutic plasma exchange (TPE) and apply a first dose of eculizumab. As soon as ADAMTS13 activity is determined further therapeutic decisions can be drawn
Taken together, CFZ-induced TMA is a serious event and should be assumed in treated MM patients with rapid acute kidney failure and hemolysis. Fast treatment initiation with eculizumab can reverse pathological complement system activation and prevent organ damage. As shown in our patients, early initiated, short-term treatment with eculizumab can sufficiently terminate CFZ-TMA and counteract TMA-poor prognostic factors.
Abbreviations
aHUSAtypical hemolytic uremic syndrome
AKINAcute kidney injury network
ASCTAutologous stem cell transplantation
BMBone marrow
CFZ-TMACarfilzomib-induced thrombotic microangiopathy
CRComplete response
DITMADrug-induced thrombotic microangiopathy
FFPFresh frozen plasma
TMAThrombotic microangiopathy
TPETherapeutic plasma exchange
TTPThrombotic thrombocytopenic purpura
MMMultiple myeloma
PCPlasma cell
PIProteasome inhibitor
STECShiga-toxin-producing E.coli
vgPRVery good partial response
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Michael Rassner, Rebecca Baur, Andreas Mackensen and Monika Engelhardt contributed equally to this work.
Acknowledgements
We would like to thank both patients for consent of publication of their educational cases within this work.
Authors’ contributions
MR and RB treated the patients, drafted and wrote the manuscript; JS, MS and RW treated the patient and revised the manuscript; AM and ME treated the patient, initiated and wrote the manuscript. All authors read and approved the final manuscript.
Funding
There was no funding received to support this research. Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
We have obtained written consent for publication from both patients presented in this case report.
Competing interests
The authors declare that they have no competing interests. | CARFILZOMIB, DEXAMETHASONE, ELOTUZUMAB, LENALIDOMIDE | DrugsGivenReaction | CC BY | 33461512 | 18,819,690 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombotic microangiopathy'. | Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma.
Treatment with proteasome inhibitors like carfilzomib in patients with multiple myeloma (MM) can induce thrombotic microangiopathy (TMA) characterized by neurological symptoms, acute kidney injury, hemolysis and thrombocytopenia. Successful treatment with the monoclonal antibody eculizumab was described for these patients, but reports of ideal management and definitive treatment protocols are lacking.
The first case describes a 43-years-old IgG-kappa-MM patient that developed TMA during the first course of carfilzomib-lenalidomide-dexamethasone (KRd) consolidation after autologous stem cell transplantation (ASCT). In the second case, a 59-years-old IgG-kappa-MM patient showed late-onset TMA during the fourth and last cycle of elotuzumab-KRd consolidation within the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Concurrently, he suffered from influenza A/B infection. Both patients had a high TMA-index for a poor prognosis of TMA. Therapeutically, in both patients plasma exchange (TPE) was initiated as soon as TMA was diagnosed. In patient #1, dialysis became necessary. For both patients, only when the complement inhibitor eculizumab was administered, kidney function and blood values impressively improved.
In this small case series, two patients with MM developed TMA due to carfilzomib treatment (CFZ-TMA), the second patient as a late-onset form. Even though TMA could have been elicited by influenza in the second patient and occurred after ASCT in both patients, with cases of TMA post-transplantation in MM being described, a relation of TMA and carfilzomib treatment was most likely. In both patients, treatment with eculizumab over two months efficiently treated TMA without recurrence and with both patients remaining responsive months after TMA onset. Taken together, we describe two cases of TMA in MM patients on carfilzomib-combination treatment, showing similar courses of this severe adverse reaction, with good responses to two months of eculizumab treatment.
Background
Thrombotic microangiopathy (TMA) is a rare cause of anemia in multiple myeloma (MM) patients, but can occasionally be elicited by common anti-myeloma drugs, especially by proteasome-inhibitors (PI) like carfilzomib (CFZ) [1–3]. Reports about TMA in MM induced by CFZ and optimal therapeutic approaches are scarce. Recently, single case reports described successful treatment of TMA in MM with the terminal complement pathway inhibitor eculizumab [1, 2, 4–6]. Definitive treatment recommendations, however, are lacking. Below we describe two cases of CFZ-induced TMA, that were successfully treated by eculizumab and provide evidence about precise therapeutic work-flow and possible interventions.
Case 1
A 43-year old male patient was diagnosed with IgG-kappa-MM in August 2018. At admission, we found extensive osteolysis and an acute kidney failure with a serum-creatinine of 4.2 mg/dl [0.67–1.17] (GFR 15 ml/min; MDRD) without previous history of impaired kidney function. With highly elevated serum free kappa light chains (kappa-SFLC) 3645 mg/l [0.35–15.10] and 4.2 g/d [< 0.15] urinary protein excretion, in the absence of albuminuria, cast nephropathy was assumed as the most likely cause of acute kidney failure. Since there was no sign of further organ injury, amyloidosis seemed unlikely, as well MIDD (monoclonal immunoglobulin deposition disease), which is often accompanied by amyloidosis and presents with albuminuria. The type of renal injury was not further determined by kidney puncture. The M-protein was elevated with 37 g/l, IgG 52.3 g/l [6.1-16.16], k/l-ratio 864 [0.46-4], hemoglobin (Hb) 9.5 g/dl [13.5–17.5], β2-microglobulin 8.7 mg/dl [0-2.34], serum calcium and LDH were normal. The bone marrow plasma cell (BMPC) infiltration was 15%, FISH excluded high-risk cytogenetics. Following the ISS grading system, we diagnosed an IgG-kappa-MM stage III (Durie & Salmon stage IIIB) and symptomatic myeloma with 3/4 CRAB criteria (anemia, renal impairment, bone lesions). The revised myeloma comorbidity index (R-MCI: 1/9 = fit/low-risk) revealed a fit patient [7–9]. Due to the CRAB-criteria, specifically renal impairment, chemotherapy was initiated with one cycle of bortezomib, doxorubicin, dexamethasone (BAD) followed by two cycles of bortezomib, cyclophosphamide, dexamethasone (VCD) after improvement of the kidney function and resolved urinary proteinuria. Since M-protein reduction was insufficient (21.4 g/l), the regimen was switched a second time to CFZ, lenalidomide and dexamethasone (KRd). After two cycles KRd, a partial remission (PR; M-protein 5.3 g/l, IgG 6.4 g/l) was achieved and high-dose melphalan (200 mg/m²) chemotherapy with autologous stem cell transplantation (ASCT) was performed. On day (d) 42 post ASCT IgG levels were increasing again (21.1 g/l). Based on the distinct improvement of the myeloma markers after KRd and a missing additional response to ASCT, our MM-tumor board decided to apply three consolidation cycles of KRd. In May 2019, the 3rd KRd cycle (1st consolidation cycle after ASCT) was initiated. At d2 of CFZ, the patient developed fever, dyspnea and malaise. Platelets were 11Tsd/µl, Hb 10.8 g/dl, LDH 1836U/l, haptoglobin < 150 mg/l, unconjugated bilirubin 2.7 mg/dl, the creatinine rose from 0.72 to 2.07 mg/dl [0.67–1.17] (GFR > 60 to 35 ml/min) (Fig. 1a) and urinary proteinuria increased from normal values to 52 g/l [< 0.135]. In the peripheral blood smear, 11‰ schistocytes were detected and an altered complement profile with reduced C3 and C4 levels was found (C3 77.6md/dl, C4 9.9 mg/dl). TMA-Index (LDH/platelets ratio) was elevated to 166. These findings (schistocytes > 10‰, elevated creatinine and TMA-Index) have been described as poor prognostic factors for transplant associated-TMA (TA-TMA) [10]. Of note, two days earlier, lab results had been normal (Fig. 1a). Chest CT scan showed bilateral infiltrates, matching pulmonary hemorrhage (Fig. 2). Due to the acute development of hemolysis, together with acute kidney injury, unsuspicious ATAMTS13 activity (61%) [50–110], normal ADAMTS13 antigen (0.48 IU/ml) [0.35–1.2] and direct Coombs test being negative, we suspected medication-induced TMA. Therapeutic plasma exchange (TPE) was initiated by replacement with fresh frozen plasma (FFP) on a daily regimen and on account of declining kidney function with development of acute kidney injury stage 3 according to the acute Kidney Injury Network (AKIN), dialysis was necessary one day later. After six days of TPE neither LDH nor platelets improved. Assuming CFZ-induced TMA, we administered eculizumab (900 mg) along with meningococcal vaccination and initiation of antibiotic prophylaxis. Five days later, LDH declined to 818U/l and platelet counts improved to 58Tsd/µl without transfusions. We continued eculizumab (900 mg) weekly. After the fourth application, dialysis could be discontinued. Platelet counts normalized within two months after treatment initiation of eculizumab and there were no further signs of TMA, thus eculizumab was terminated (Fig. 1a). One year after TMA diagnosis and KRd consolidation, our patient remains in PR of his MM and CR of the CFZ-induced TMA.
Fig. 1 Course of CFZ-TMA in the two patients. a Case #1: This patient developed acute kidney injury, fever and pulmonary hemorrhage during the first consolidation with carfilzomib, lenalidomide and dexamethasone (KRd) after ASCT. Laboratory findings (thrombocytopenia) and schistocytosis of 11‰ were consistent with thrombotic microangiopathy (TMA). Therapeutic plasma exchange (TPE) was immediately initiated, but shortly after dialysis was necessary. As blood values did not improve, we finally administered eculizumab for a total of seven doses and saw a rapid response in LDH, platelet number and kidney function with our patient being still in PR. b Case #2: This patient, who is treated in the DSMM XVII study (Arm A: Elotuzumab-KRd) developed head ache, malignant hypertension and laboratory distortions (thrombocytopenia, increase of LDH and acute kidney injury) consistent with TMA. After a short period of TPE, eculizumab was infused (total of six infusions). Blood values improved but kidney function remains decreased
Fig. 2 a Chest-CT in patient case 1, d1 of CFZ-TMA onset: Bipulmonary extensive ground-glass opacities in all lung fields, mostly omitting the periphery and predominantly occurring in the right lung. b Mechanism of CFZ-TMA: Within the proximal complement activation C3 is cleaved by the C3 convertase to anaphylactic 3a and C3b. C3b then cleaves C5 to C5a and C5b, the latter together with C6-C9 forming the membrane attack complex (MAC) within the terminal pathway. Activity of the C3 convertase is regulated by complement factor H and regulated proteins. Proteasome inhibition blocks CFH [11]. The monoclonal antibody eculizumab counteracts the resulting overactivation of C3b by binding C5
Case 2
The second 59-year-old male patient was diagnosed with IgG-kappa-MM in 11/2018. CT scan revealed osteolysis of the sacrum, pelvis and vertebrae. Calcium and creatinine were normal and the Hb was slightly decreased (13.3 g/dl). IgG was 38.4 g/l, k-SFLC 182 mg/l, k/l-ratio 60.5. BM biopsy revealed 40% PC infiltration. Cytogenetics were favorable (trisomy 5p15, 9q22, 11q13 und 15q22). The ISS and R-ISS were both I, Durie & Salmon stage was IIIA and symptomatic MM was diagnosed with 1/4 CRAB symptoms. The patient was classified as fit for ASCT (R-MCI-score: 2/9 = fit) [7–9]. We included the patient into the DSMM XVII study of the German study group MM (DSMM; clinicalTrials.gov Identifier: NCT03948035). Induction with elotuzumab, CFZ, lenalidomide and dexamethasone (E-KRd, 6 cycles) and ASCT with melphalan 200 mg/m2 were performed and due to repeated respiratory infections (boca- and corona (CoV NL 63) virus) dose reductions of elotuzumab and lenalidomide were executed. Before ASCT, kappa-SFLC decreased to 12.8 mg/l (vgPR).
In 01/20, within the last (4th) cycle of E-KRd consolidation, the patient developed fever and acute kidney failure with creatinine 1.7 mg/dl (GFR 40 ml/min, MRDRD; baseline-creatinine: 1 mg/dl). Prerenal genesis was assumed (fractional sodium excretion < 1%) and fluids were infused. However, creatinine elevation did not resolve finally reaching acute kidney injury stage 3 according to AKIN and proteinuria reached 6.2 g/d. The patient developed headache and high blood pressure (BP 220/105 mmHg). Platelets and Hb gradually decreased (Fig. 1b), haptoglobin was < 5 mg/dl. In the peripheral blood smear, 44‰ schistocytes were visible; ADAMTS13 activity and antigen were normal (58% and 0.40 IU/ml, respectively) and Coombs test negative. Blood culture additionally showed Staphylococcus epidermidis due to port infection and throat swab detected influenza A (H3N2) and B.
Since TMA was diagnosed (LDH/platelets ratio 88.3), high-dose glucocorticoids and TPE were applied (before completion of diagnostics). Without substantial improvement, five days after first plasmapheresis our patient received eculizumab (Fig. 1b), starting at 900 mg. A total of 11 sessions of plasma exchange at a daily basis were performed with FFP as replacement (Fig. 1b). Parameters of hemolysis rapidly improved, so that glucocorticoids could be expeditiously reduced and eculizumab was terminated after four cycles with 900 mg/weekly and two doses with 1200 mg/every two weeks (Fig. 1b).
In 05/19, the patient showed VGPR of his MM, the BMPC infiltration even CR (polyclonal PCs of 5%) and gradual renal function improvement (eGFR improved from 10 to 32 ml/min). Maintenance therapy with reduced doses of elotuzumab-lenalidomide (E-R: lenalidomide with 5 mg d1-28) was successfully initiated and TMA has remained in CR.
Discussion and conclusion
Hemolysis is a rather rare cause for anemia in MM [12]. When anemia is accompanied with thrombocytopenia, acute kidney injury, high blood pressure, neurological or unexplained extrarenal symptoms TMA should be considered. TMA includes a group of etiologically diverse diseases: Primary TMA, which include atypical HUS (aHUS) or thrombotic thrombocytopenic purpura (TTP) and secondary TMA and infection-associated TMA, involving Shiga-toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) [6, 13, 14]. TTP, in contrast to other TMA forms, is defined by decreased activity of the vWF-cleaving enzyme ADAMTS13 [6]. Unlike “typical” HUS, which is triggered by infections with STEC, complement mediated TMA is driven by uncontrolled complement activation and affected patients frequently harbor mutations in complement regulatory proteins (Fig. 2b) [15]. Secondary TMA is elicited by medication, malignancy, pregnancy, malignant hypertension, transplantations, infections or associated to autoimmune diseases [6, 10, 12–14]. As reviewed recently [6], TMA in MM can be elicited by ASCT- or allogeneic-SCT, MM progression, or anti-myeloma therapy. Drug-induced TMA (DITMA) may occur in MM due to PIs bortezomib or CFZ [3, 16, 17]. CFZ-TMA can appear early after onset of the drug, but also as late as two years after first administration [1, 2]. CFZ-TMA is probably driven by complement activation of the alternative pathway in terms of complement-mediated TMA [2–4, 18]. Blasco et al. described three cases in which plasma samples from patients with CFZ-TMA, led to depositions of complex membrane attack complex (C5b-9) of on endothelial cells, suggesting a complement overactivation [4]. Supporting this assumption, proteasome inhibition has been found to block Factor H, consequently leading to complement activation (Fig. 2b) [11]. Bortezomib-induced cases of TMA are attributed to decreased activity of ADAMTS13 [19, 20]. However, the majority of bortezomib-induced cases of TMA/TTP had only slightly decreased ADAMTS13 activity and PI-induced TMA in MM might be generally based on pathological overactivation of the alternative complement pathway rather than TTP [6]. In patient #2, TMA was either induced by CFZ or influenza A or B [15, 21]. Also a combination of both preexistent vascular endothelial injury due to CFZ and transient complement activation during influenza infection was eagerly discussed within our group. In this respect, eculizumab could be effective in patients treated with concurrent PI treatment, infection and TMA.
In patient #2, in contrast to patient #1, C3 and C4 levels were normal; CH50 and C5b-9, the terminal pathway of the complement pathway were, however, not assessed. The fast response to eculizumab and the lacking effect of TPE seemed to argue for pathological complement activation, but it cannot be ruled out that the classical or the alternative complement pathway was involved. Importantly, both patients developed TMA several weeks after ASCT. Since TA-TMA was described to occur in a complement-dependent manner, like complement mediated TMA [10], a combination of TMA-triggers is likewise conceivable.
Taken together, several factors might have induced TMA in our patients: ASCT, genetic predispositions, viral infections and the underlying CFZ treatment. Thus, definite causality could ot be entirely proven. The major criticism of our study may be missing additional in vitro studies of complement activation and the unavailability of renal biopsies for further diagnostics. Kidney biopsies had been discussed interdisciplinary in our weekly MM tumor board, however, in the acute clinical setting, the potential biopsy risk, especially bleeding, was judged to outweigh potential benefits and on top, both patients had declined kidney biopsies.
In respect to therapy for TMA in MM, definitive clinical practical guidelines do not exist [6]. For DITMA, the causative drug must be discontinued promptly, high-dose glucocorticoids are given and plasmapheresis is performed [2, 6]. In CFZ-TMA, successful treatment with eculizumab, a terminal complement pathway inhibitor, was described in six cases to our knowledge [1, 2, 4, 5, 22]. Nevertheless, reports of TMA in MM remain scarce, and the definitive treatment regimen as well as definitive duration of treatment are unclear [6]: Portuguese and Lipe (2018), Moliz et al. (2019) and Blasco et al. (2020) administered eculizumab for up to three weekly doses [2, 4, 22], whereas Bhutani et al. (2020) for four months [1]. In our two cases, only after eculizumab initiation, hemolysis and creatinine levels improved impressively (Fig. 1A,B), plus the application period of two months of eculizumab was efficient without relapsing TMA, thus appears possible to be shorter than four months. On the other hand a shorter treatment period, as reported by Portuguese and Lipe, might be insufficient as one of their eculizumab-treated patients stayed on hemodialysis with this regime [22].
TPE is generally recommended for TMA. Plasma exchange, however, is not without side effects, and can remove therapeutic antibodies from the circulation, thus its concurrent use is not recommended [6, 10]. Interestingly, in our cases the success of eculizumab was not fully dependent on the termination of TPE, since in patient #2 TPE was continued during the first two eculizumab doses. In this respect, concerns, that TPE would remove eculizumab from the blood or restore C5-levels available for activation, seem unfounded. On the other hand, a significant improvement of creatinine-levels and platelets was only achieved after termination of TPE in patient #2 (Fig. 1B). Thus, irrespective of the cause of TMA in MM patients under PI treatment or shortly after ASCT, eculizumab rather than TPE could be considered as standard first-line therapy [2, 6] (Fig. 3). Increased susceptibility to meningococcal infection during eculizumab treatment has to be considered and vaccination should be implemented [23]. As soon as ADAMTS13 activity is proven to be within the normal range (50–150%) and TTP is excluded, further treatment decisions can be drawn [6]. Additionally, in our experience short-term use of eculizumab was sufficient for effective TMA treatment. Furthermore, eculizumab treatment did not worsen MM parameters in neither of our patients.
Fig. 3 Guideline for diagnostic and therapeutic approach for TMA in MM: Whenever clinical and laboratory findings are consistent with TMA, one should rapidly terminate possible causative drugs, initiate therapeutic plasma exchange (TPE) and apply a first dose of eculizumab. As soon as ADAMTS13 activity is determined further therapeutic decisions can be drawn
Taken together, CFZ-induced TMA is a serious event and should be assumed in treated MM patients with rapid acute kidney failure and hemolysis. Fast treatment initiation with eculizumab can reverse pathological complement system activation and prevent organ damage. As shown in our patients, early initiated, short-term treatment with eculizumab can sufficiently terminate CFZ-TMA and counteract TMA-poor prognostic factors.
Abbreviations
aHUSAtypical hemolytic uremic syndrome
AKINAcute kidney injury network
ASCTAutologous stem cell transplantation
BMBone marrow
CFZ-TMACarfilzomib-induced thrombotic microangiopathy
CRComplete response
DITMADrug-induced thrombotic microangiopathy
FFPFresh frozen plasma
TMAThrombotic microangiopathy
TPETherapeutic plasma exchange
TTPThrombotic thrombocytopenic purpura
MMMultiple myeloma
PCPlasma cell
PIProteasome inhibitor
STECShiga-toxin-producing E.coli
vgPRVery good partial response
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Michael Rassner, Rebecca Baur, Andreas Mackensen and Monika Engelhardt contributed equally to this work.
Acknowledgements
We would like to thank both patients for consent of publication of their educational cases within this work.
Authors’ contributions
MR and RB treated the patients, drafted and wrote the manuscript; JS, MS and RW treated the patient and revised the manuscript; AM and ME treated the patient, initiated and wrote the manuscript. All authors read and approved the final manuscript.
Funding
There was no funding received to support this research. Open Access funding enabled and organized by Projekt DEAL.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Not applicable.
Consent for publication
We have obtained written consent for publication from both patients presented in this case report.
Competing interests
The authors declare that they have no competing interests. | CARFILZOMIB, DEXAMETHASONE, ELOTUZUMAB, LENALIDOMIDE | DrugsGivenReaction | CC BY | 33461512 | 18,819,690 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease recurrence'. | Tolosa-Hunt syndrome relapse during pregnancy following chronic intake of combined oral contraceptives.
Tolosa-Hunt syndrome (THS) is a rare syndrome of painful ophthalmoplegia secondary to an idiopathic granulomatous inflammation affecting the cavernous sinus, superior orbital fissure or orbit. Pregnancy and pregnancy-related hormones have been identified as potential triggers. A 39-year-old gravida-2 para-1 woman with prior chronic intake of combined oral contraceptives (COC) suffered two episodes of painful ophthalmoplegia-the first event with spontaneous remission and the relapse occurring during pregnancy and with complete resolution following steroid treatment. MRI revealed a postinflammatory mass at the junction of the left orbital apex and anterior cavernous sinus, supporting the diagnosis of THS. To our knowledge, this is the first report of a THS relapse occurring during pregnancy following a chronic history of COC intake. This case adds to the growing evidence supporting the relationship between immune and hormonal factors that may be present during pregnancy and the disease pathogenesis of THS.
BACKGROUND
Tolosa-Hunt syndrome (THS) is a rare condition characterised by painful ophthalmoplegia attributed to an idiopathic granulomatous inflammation of the cavernous sinus, superior orbital fissure or orbit.1 It has an estimated incidence of nearly one to two cases per million per year and is ultimately a diagnosis of exclusion.2 While its aetiology remains unknown, few reports in the literature have documented its dysimmune pathogenesis influenced by pregnancy and pregnancy-related hormones.3 4
Case presentation
A 39-year-old gravida-2 para-1 woman with a known history of hypertension presented at our institution pregnant at 31 2/7 weeks of gestation with sudden-onset, moderate-to-severe left temporal headache radiating to the orbital-periorbital area with ipsilateral abduction deficit, binocular diplopia, tearing and blurring of vision. This occurred following a chronic history of combined oral contraceptive (COC) intake containing ethinyl oestradiol and levonorgestrel for 7 years. She reported a similar event of painful ophthalmoplegia that occurred 2 years earlier that spontaneously resolved 6 weeks after symptom onset. Examination at the time of admission revealed left esotropia, left lateral rectus palsy and elevated blood pressures. Visual function and fundus examination demonstrated bilateral error of refraction and grade II hypertensive retinopathy. There was no objective sensory deficit on the left side of the face, proptosis or signs of Horner syndrome. Temporary and slight relief of pain was reported with normalisation of blood pressure and administration of intramuscular dexamethasone given for fetal lung maturity. However, the patient’s ophthalmoplegia did not improve.
Investigations
Initial workup revealed an elevated erythrocyte sedimentation rate of 60 mm/hour, mild leucocytosis of 15.50×109/L on complete blood count and proteinuria of more than 0.3 g on 24-hour urine protein measurement. Baseline serum electrolytes and coagulation profile were normal. Cerebrospinal fluid (CSF) studies, which included aerobic cultures, cytology, and tests for fungal and tuberculous infections, were unremarkable. Thyroid function tests were normal and antidouble stranded DNA and anticonnective tissue disease antibody tests were negative. Screening for diabetes mellitus with glycated haemoglobin and fasting blood sugar was unremarkable. Serum and CSF rapid plasma reagin results to screen for syphilis were normal. Brain MRI showed a small, T1 hyperintense, T2/fluid-attenuated inversion recovery isointense soft tissue focus with minimal gadolinium enhancement at the junction of the left orbital apex and anterior cavernous sinus, compatible with granulomatous inflammation (figure 1). The left orbit was also oriented medially and there was atrophy of the left lateral rectus muscle. MR angiography was unremarkable, other than a hypolastic/absent A1 segment of the right anterior cerebral artery, which may be a normal anatomical variant.
Figure 1 (A) T1-weighted non-contrast, (B) T1-weighted contrast and (C) T2-weighted brain MRI images in axial cuts showing the postinflammatory mass lesion (arrow) at the junction of the left orbital apex and anterior cavernous sinus. Images were generated using a gadolinium-based contrast agent.
Differential diagnosis
The diagnosis of THS was based on the unilateral orbital-periorbital headache developing with a paresis of the ipsilateral sixth cranial nerve, granulomatous inflammation at the junction of the orbital apex and anterior cavernous sinus demonstrated by MRI, and absence of other clinical or radiographic signs or symptoms fulfilling the International Classification of Headache Disorders.5 Vascular aetiologies, such as a carotid aneurysm or diabetic or arteritic infarction, as differential diagnoses were less likely based on cranial imaging and negative screening tests for diabetes mellitus. Infectious causes, such as focal abscesses, syphilitic pachymeningitis or tuberculous meningoencephalitis, were ruled out due to the absence of characteristic meningeal signs or systemic signs of infection as well as the unremarkable blood and CSF findings. Neoplasms, such as lymphoma, meningioma or nasopharyngeal carcinoma, were considered but ruled out due to uncharacteristic cranial imaging coupled with negative CSF findings. Moreover, the lack of orbital signs pointing to a mechanical restriction, such as in thyroid orbitopathy or orbital pseudotumor, and negative thyroid function tests rule out these considerations. Based on her elevated blood pressure and total urine protein, the patient was also managed obstetrically as a case of chronic hypertension with superimposed pre-eclampsia with severe features.
Treatment, outcome and follow-up
Labour was induced, and due to a non-reassuring fetal status, an uncomplicated caesarean delivery followed. After delivery, the patient completed prednisone 80 mg daily dose for 3 days, with gradual down-tapering by 20 mg every 2 weeks thereafter; this resulted in progressive alleviation and subsequent complete resolution of the patient’s headache and ophthalmoplegia after 5 weeks. On follow-up after 6 months, there was no reported recurrence.
Discussion
THS is characterised by a non-specific lymphoplasmacytic inflammation of the septa and wall of the cavernous sinus, associated with proliferation of fibroblasts, epithelioid cells and occasional giant cells.6 7 The exact cause of this inflammatory process remains unknown. There seems to be no consistent link to an infectious organism.8 Few associations with other inflammatory disorders, such as systemic lupus erythematosus (SLE), Hashimoto thyroiditis, Hodgkin lymphoma and rheumatoid polyarthritis, have been reported; hence, an autoimmune aetiology has been suggested, but is still unclear.9 Traumatic injury has also been associated as a potential trigger for THS.10 To date, only two cases of THS occurring during pregnancy have been reported in the literature. Levin and Karussis (2002) first reported a 32-year-old woman with two episodes of THS, both of which were linked to changes in gonadal hormone levels—the onset triggered by clomiphene treatment and the relapse triggered by progesterone treatment during pregnancy.4 A second report by Litwin and Leung (2017) described a case of a 24-year-old woman who presented with THS during pregnancy following progesterone administration for first-trimester bleeding.3
Virtually every organ system undergoes changes during pregnancy, including the immune system. These immune responses contribute to the outcome of pregnancy and to disease pathogenesis as well.11 The complex tolerance that exists at the maternal-fetal interface is in part due to the physiological suppression of various immunological functions.12 During pregnancy, there is a functional shift of CD4 T lymphocyte subpopulations towards T helper cells (Th)2-mediated immunity and an increased secretion of the Th2 cytokines—interleukin (IL) 4, IL-10, IL-13.4 Therefore, while suppression of Th1-mediated immunity is an important anti-inflammatory component of pregnancy, promotion of antibody-based immunity by Th2 cytokines has resulted in flares of autoimmune diseases mediated mainly by autoantibodies, such as SLE.12
Pregnancy-related hormones also exert immunological changes. Progesterone has been shown to inhibit the development of Th1 immune responses and promote Th2 cytokine secretion.11 13 The differential effects of oestrogen are partly determined by its concentration: low or physiological doses of oestradiol promote Th1 responses and enhance secretion of proinflammatory cytokines (eg, IL-1, IL-6 and tumour necrosis factor-α (TNF-α)), whereas high or pregnancy doses augment Th2 responses and reduce the production of these cytokines.11 With reduced expression of TNF-α, which could be neurotoxic, oestrogen offers a neuroprotective effect.14 Interestingly, however, attenuation of TNF-α by pregnancy-levels of oestrogen and progesterone has also been shown to further promote granuloma formation by decreasing TNF-induced-apoptosis of granuloma cells.15 The shielding effect of these hormones, along with their enhanced expression of angiogenic factors, implicates their importance in the pathogenesis of uncontrolled inflammation and may prove relevant in the pathogenesis of THS.3 15
In this patient, the chronic administration of combined oestrogen and progesterone on top of the immunomodulating effects of pregnancy could have precipitated her episodes of THS. To our knowledge, this is the first report of a THS relapse occurring during pregnancy following a chronic history of COC intake. This case adds to the growing evidence supporting the interplay between immune and hormonal factors and the disease pathogenesis of THS.
Learning points
Pregnancy and pregnancy-related hormones have been identified as potential triggers of Tolosa-Hunt syndrome (THS).
Immune response during pregnancy contributes to disease pathogenesis.
Oestrogen and progesterone may prove relevant in the pathogenesis of THS.
Contributors: BLCP: Research project: conception, organisation, execution. Manuscript preparation: writing of the first draft. KLO and ARC: Manuscript preparation: review and critique.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | ETHINYL ESTRADIOL, LEVONORGESTREL | DrugsGivenReaction | CC BY-NC | 33462037 | 19,145,964 | 2021-01-18 |
What was the administration route of drug 'ETHINYL ESTRADIOL'? | Tolosa-Hunt syndrome relapse during pregnancy following chronic intake of combined oral contraceptives.
Tolosa-Hunt syndrome (THS) is a rare syndrome of painful ophthalmoplegia secondary to an idiopathic granulomatous inflammation affecting the cavernous sinus, superior orbital fissure or orbit. Pregnancy and pregnancy-related hormones have been identified as potential triggers. A 39-year-old gravida-2 para-1 woman with prior chronic intake of combined oral contraceptives (COC) suffered two episodes of painful ophthalmoplegia-the first event with spontaneous remission and the relapse occurring during pregnancy and with complete resolution following steroid treatment. MRI revealed a postinflammatory mass at the junction of the left orbital apex and anterior cavernous sinus, supporting the diagnosis of THS. To our knowledge, this is the first report of a THS relapse occurring during pregnancy following a chronic history of COC intake. This case adds to the growing evidence supporting the relationship between immune and hormonal factors that may be present during pregnancy and the disease pathogenesis of THS.
BACKGROUND
Tolosa-Hunt syndrome (THS) is a rare condition characterised by painful ophthalmoplegia attributed to an idiopathic granulomatous inflammation of the cavernous sinus, superior orbital fissure or orbit.1 It has an estimated incidence of nearly one to two cases per million per year and is ultimately a diagnosis of exclusion.2 While its aetiology remains unknown, few reports in the literature have documented its dysimmune pathogenesis influenced by pregnancy and pregnancy-related hormones.3 4
Case presentation
A 39-year-old gravida-2 para-1 woman with a known history of hypertension presented at our institution pregnant at 31 2/7 weeks of gestation with sudden-onset, moderate-to-severe left temporal headache radiating to the orbital-periorbital area with ipsilateral abduction deficit, binocular diplopia, tearing and blurring of vision. This occurred following a chronic history of combined oral contraceptive (COC) intake containing ethinyl oestradiol and levonorgestrel for 7 years. She reported a similar event of painful ophthalmoplegia that occurred 2 years earlier that spontaneously resolved 6 weeks after symptom onset. Examination at the time of admission revealed left esotropia, left lateral rectus palsy and elevated blood pressures. Visual function and fundus examination demonstrated bilateral error of refraction and grade II hypertensive retinopathy. There was no objective sensory deficit on the left side of the face, proptosis or signs of Horner syndrome. Temporary and slight relief of pain was reported with normalisation of blood pressure and administration of intramuscular dexamethasone given for fetal lung maturity. However, the patient’s ophthalmoplegia did not improve.
Investigations
Initial workup revealed an elevated erythrocyte sedimentation rate of 60 mm/hour, mild leucocytosis of 15.50×109/L on complete blood count and proteinuria of more than 0.3 g on 24-hour urine protein measurement. Baseline serum electrolytes and coagulation profile were normal. Cerebrospinal fluid (CSF) studies, which included aerobic cultures, cytology, and tests for fungal and tuberculous infections, were unremarkable. Thyroid function tests were normal and antidouble stranded DNA and anticonnective tissue disease antibody tests were negative. Screening for diabetes mellitus with glycated haemoglobin and fasting blood sugar was unremarkable. Serum and CSF rapid plasma reagin results to screen for syphilis were normal. Brain MRI showed a small, T1 hyperintense, T2/fluid-attenuated inversion recovery isointense soft tissue focus with minimal gadolinium enhancement at the junction of the left orbital apex and anterior cavernous sinus, compatible with granulomatous inflammation (figure 1). The left orbit was also oriented medially and there was atrophy of the left lateral rectus muscle. MR angiography was unremarkable, other than a hypolastic/absent A1 segment of the right anterior cerebral artery, which may be a normal anatomical variant.
Figure 1 (A) T1-weighted non-contrast, (B) T1-weighted contrast and (C) T2-weighted brain MRI images in axial cuts showing the postinflammatory mass lesion (arrow) at the junction of the left orbital apex and anterior cavernous sinus. Images were generated using a gadolinium-based contrast agent.
Differential diagnosis
The diagnosis of THS was based on the unilateral orbital-periorbital headache developing with a paresis of the ipsilateral sixth cranial nerve, granulomatous inflammation at the junction of the orbital apex and anterior cavernous sinus demonstrated by MRI, and absence of other clinical or radiographic signs or symptoms fulfilling the International Classification of Headache Disorders.5 Vascular aetiologies, such as a carotid aneurysm or diabetic or arteritic infarction, as differential diagnoses were less likely based on cranial imaging and negative screening tests for diabetes mellitus. Infectious causes, such as focal abscesses, syphilitic pachymeningitis or tuberculous meningoencephalitis, were ruled out due to the absence of characteristic meningeal signs or systemic signs of infection as well as the unremarkable blood and CSF findings. Neoplasms, such as lymphoma, meningioma or nasopharyngeal carcinoma, were considered but ruled out due to uncharacteristic cranial imaging coupled with negative CSF findings. Moreover, the lack of orbital signs pointing to a mechanical restriction, such as in thyroid orbitopathy or orbital pseudotumor, and negative thyroid function tests rule out these considerations. Based on her elevated blood pressure and total urine protein, the patient was also managed obstetrically as a case of chronic hypertension with superimposed pre-eclampsia with severe features.
Treatment, outcome and follow-up
Labour was induced, and due to a non-reassuring fetal status, an uncomplicated caesarean delivery followed. After delivery, the patient completed prednisone 80 mg daily dose for 3 days, with gradual down-tapering by 20 mg every 2 weeks thereafter; this resulted in progressive alleviation and subsequent complete resolution of the patient’s headache and ophthalmoplegia after 5 weeks. On follow-up after 6 months, there was no reported recurrence.
Discussion
THS is characterised by a non-specific lymphoplasmacytic inflammation of the septa and wall of the cavernous sinus, associated with proliferation of fibroblasts, epithelioid cells and occasional giant cells.6 7 The exact cause of this inflammatory process remains unknown. There seems to be no consistent link to an infectious organism.8 Few associations with other inflammatory disorders, such as systemic lupus erythematosus (SLE), Hashimoto thyroiditis, Hodgkin lymphoma and rheumatoid polyarthritis, have been reported; hence, an autoimmune aetiology has been suggested, but is still unclear.9 Traumatic injury has also been associated as a potential trigger for THS.10 To date, only two cases of THS occurring during pregnancy have been reported in the literature. Levin and Karussis (2002) first reported a 32-year-old woman with two episodes of THS, both of which were linked to changes in gonadal hormone levels—the onset triggered by clomiphene treatment and the relapse triggered by progesterone treatment during pregnancy.4 A second report by Litwin and Leung (2017) described a case of a 24-year-old woman who presented with THS during pregnancy following progesterone administration for first-trimester bleeding.3
Virtually every organ system undergoes changes during pregnancy, including the immune system. These immune responses contribute to the outcome of pregnancy and to disease pathogenesis as well.11 The complex tolerance that exists at the maternal-fetal interface is in part due to the physiological suppression of various immunological functions.12 During pregnancy, there is a functional shift of CD4 T lymphocyte subpopulations towards T helper cells (Th)2-mediated immunity and an increased secretion of the Th2 cytokines—interleukin (IL) 4, IL-10, IL-13.4 Therefore, while suppression of Th1-mediated immunity is an important anti-inflammatory component of pregnancy, promotion of antibody-based immunity by Th2 cytokines has resulted in flares of autoimmune diseases mediated mainly by autoantibodies, such as SLE.12
Pregnancy-related hormones also exert immunological changes. Progesterone has been shown to inhibit the development of Th1 immune responses and promote Th2 cytokine secretion.11 13 The differential effects of oestrogen are partly determined by its concentration: low or physiological doses of oestradiol promote Th1 responses and enhance secretion of proinflammatory cytokines (eg, IL-1, IL-6 and tumour necrosis factor-α (TNF-α)), whereas high or pregnancy doses augment Th2 responses and reduce the production of these cytokines.11 With reduced expression of TNF-α, which could be neurotoxic, oestrogen offers a neuroprotective effect.14 Interestingly, however, attenuation of TNF-α by pregnancy-levels of oestrogen and progesterone has also been shown to further promote granuloma formation by decreasing TNF-induced-apoptosis of granuloma cells.15 The shielding effect of these hormones, along with their enhanced expression of angiogenic factors, implicates their importance in the pathogenesis of uncontrolled inflammation and may prove relevant in the pathogenesis of THS.3 15
In this patient, the chronic administration of combined oestrogen and progesterone on top of the immunomodulating effects of pregnancy could have precipitated her episodes of THS. To our knowledge, this is the first report of a THS relapse occurring during pregnancy following a chronic history of COC intake. This case adds to the growing evidence supporting the interplay between immune and hormonal factors and the disease pathogenesis of THS.
Learning points
Pregnancy and pregnancy-related hormones have been identified as potential triggers of Tolosa-Hunt syndrome (THS).
Immune response during pregnancy contributes to disease pathogenesis.
Oestrogen and progesterone may prove relevant in the pathogenesis of THS.
Contributors: BLCP: Research project: conception, organisation, execution. Manuscript preparation: writing of the first draft. KLO and ARC: Manuscript preparation: review and critique.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33462037 | 19,145,964 | 2021-01-18 |
What was the administration route of drug 'LEVONORGESTREL'? | Tolosa-Hunt syndrome relapse during pregnancy following chronic intake of combined oral contraceptives.
Tolosa-Hunt syndrome (THS) is a rare syndrome of painful ophthalmoplegia secondary to an idiopathic granulomatous inflammation affecting the cavernous sinus, superior orbital fissure or orbit. Pregnancy and pregnancy-related hormones have been identified as potential triggers. A 39-year-old gravida-2 para-1 woman with prior chronic intake of combined oral contraceptives (COC) suffered two episodes of painful ophthalmoplegia-the first event with spontaneous remission and the relapse occurring during pregnancy and with complete resolution following steroid treatment. MRI revealed a postinflammatory mass at the junction of the left orbital apex and anterior cavernous sinus, supporting the diagnosis of THS. To our knowledge, this is the first report of a THS relapse occurring during pregnancy following a chronic history of COC intake. This case adds to the growing evidence supporting the relationship between immune and hormonal factors that may be present during pregnancy and the disease pathogenesis of THS.
BACKGROUND
Tolosa-Hunt syndrome (THS) is a rare condition characterised by painful ophthalmoplegia attributed to an idiopathic granulomatous inflammation of the cavernous sinus, superior orbital fissure or orbit.1 It has an estimated incidence of nearly one to two cases per million per year and is ultimately a diagnosis of exclusion.2 While its aetiology remains unknown, few reports in the literature have documented its dysimmune pathogenesis influenced by pregnancy and pregnancy-related hormones.3 4
Case presentation
A 39-year-old gravida-2 para-1 woman with a known history of hypertension presented at our institution pregnant at 31 2/7 weeks of gestation with sudden-onset, moderate-to-severe left temporal headache radiating to the orbital-periorbital area with ipsilateral abduction deficit, binocular diplopia, tearing and blurring of vision. This occurred following a chronic history of combined oral contraceptive (COC) intake containing ethinyl oestradiol and levonorgestrel for 7 years. She reported a similar event of painful ophthalmoplegia that occurred 2 years earlier that spontaneously resolved 6 weeks after symptom onset. Examination at the time of admission revealed left esotropia, left lateral rectus palsy and elevated blood pressures. Visual function and fundus examination demonstrated bilateral error of refraction and grade II hypertensive retinopathy. There was no objective sensory deficit on the left side of the face, proptosis or signs of Horner syndrome. Temporary and slight relief of pain was reported with normalisation of blood pressure and administration of intramuscular dexamethasone given for fetal lung maturity. However, the patient’s ophthalmoplegia did not improve.
Investigations
Initial workup revealed an elevated erythrocyte sedimentation rate of 60 mm/hour, mild leucocytosis of 15.50×109/L on complete blood count and proteinuria of more than 0.3 g on 24-hour urine protein measurement. Baseline serum electrolytes and coagulation profile were normal. Cerebrospinal fluid (CSF) studies, which included aerobic cultures, cytology, and tests for fungal and tuberculous infections, were unremarkable. Thyroid function tests were normal and antidouble stranded DNA and anticonnective tissue disease antibody tests were negative. Screening for diabetes mellitus with glycated haemoglobin and fasting blood sugar was unremarkable. Serum and CSF rapid plasma reagin results to screen for syphilis were normal. Brain MRI showed a small, T1 hyperintense, T2/fluid-attenuated inversion recovery isointense soft tissue focus with minimal gadolinium enhancement at the junction of the left orbital apex and anterior cavernous sinus, compatible with granulomatous inflammation (figure 1). The left orbit was also oriented medially and there was atrophy of the left lateral rectus muscle. MR angiography was unremarkable, other than a hypolastic/absent A1 segment of the right anterior cerebral artery, which may be a normal anatomical variant.
Figure 1 (A) T1-weighted non-contrast, (B) T1-weighted contrast and (C) T2-weighted brain MRI images in axial cuts showing the postinflammatory mass lesion (arrow) at the junction of the left orbital apex and anterior cavernous sinus. Images were generated using a gadolinium-based contrast agent.
Differential diagnosis
The diagnosis of THS was based on the unilateral orbital-periorbital headache developing with a paresis of the ipsilateral sixth cranial nerve, granulomatous inflammation at the junction of the orbital apex and anterior cavernous sinus demonstrated by MRI, and absence of other clinical or radiographic signs or symptoms fulfilling the International Classification of Headache Disorders.5 Vascular aetiologies, such as a carotid aneurysm or diabetic or arteritic infarction, as differential diagnoses were less likely based on cranial imaging and negative screening tests for diabetes mellitus. Infectious causes, such as focal abscesses, syphilitic pachymeningitis or tuberculous meningoencephalitis, were ruled out due to the absence of characteristic meningeal signs or systemic signs of infection as well as the unremarkable blood and CSF findings. Neoplasms, such as lymphoma, meningioma or nasopharyngeal carcinoma, were considered but ruled out due to uncharacteristic cranial imaging coupled with negative CSF findings. Moreover, the lack of orbital signs pointing to a mechanical restriction, such as in thyroid orbitopathy or orbital pseudotumor, and negative thyroid function tests rule out these considerations. Based on her elevated blood pressure and total urine protein, the patient was also managed obstetrically as a case of chronic hypertension with superimposed pre-eclampsia with severe features.
Treatment, outcome and follow-up
Labour was induced, and due to a non-reassuring fetal status, an uncomplicated caesarean delivery followed. After delivery, the patient completed prednisone 80 mg daily dose for 3 days, with gradual down-tapering by 20 mg every 2 weeks thereafter; this resulted in progressive alleviation and subsequent complete resolution of the patient’s headache and ophthalmoplegia after 5 weeks. On follow-up after 6 months, there was no reported recurrence.
Discussion
THS is characterised by a non-specific lymphoplasmacytic inflammation of the septa and wall of the cavernous sinus, associated with proliferation of fibroblasts, epithelioid cells and occasional giant cells.6 7 The exact cause of this inflammatory process remains unknown. There seems to be no consistent link to an infectious organism.8 Few associations with other inflammatory disorders, such as systemic lupus erythematosus (SLE), Hashimoto thyroiditis, Hodgkin lymphoma and rheumatoid polyarthritis, have been reported; hence, an autoimmune aetiology has been suggested, but is still unclear.9 Traumatic injury has also been associated as a potential trigger for THS.10 To date, only two cases of THS occurring during pregnancy have been reported in the literature. Levin and Karussis (2002) first reported a 32-year-old woman with two episodes of THS, both of which were linked to changes in gonadal hormone levels—the onset triggered by clomiphene treatment and the relapse triggered by progesterone treatment during pregnancy.4 A second report by Litwin and Leung (2017) described a case of a 24-year-old woman who presented with THS during pregnancy following progesterone administration for first-trimester bleeding.3
Virtually every organ system undergoes changes during pregnancy, including the immune system. These immune responses contribute to the outcome of pregnancy and to disease pathogenesis as well.11 The complex tolerance that exists at the maternal-fetal interface is in part due to the physiological suppression of various immunological functions.12 During pregnancy, there is a functional shift of CD4 T lymphocyte subpopulations towards T helper cells (Th)2-mediated immunity and an increased secretion of the Th2 cytokines—interleukin (IL) 4, IL-10, IL-13.4 Therefore, while suppression of Th1-mediated immunity is an important anti-inflammatory component of pregnancy, promotion of antibody-based immunity by Th2 cytokines has resulted in flares of autoimmune diseases mediated mainly by autoantibodies, such as SLE.12
Pregnancy-related hormones also exert immunological changes. Progesterone has been shown to inhibit the development of Th1 immune responses and promote Th2 cytokine secretion.11 13 The differential effects of oestrogen are partly determined by its concentration: low or physiological doses of oestradiol promote Th1 responses and enhance secretion of proinflammatory cytokines (eg, IL-1, IL-6 and tumour necrosis factor-α (TNF-α)), whereas high or pregnancy doses augment Th2 responses and reduce the production of these cytokines.11 With reduced expression of TNF-α, which could be neurotoxic, oestrogen offers a neuroprotective effect.14 Interestingly, however, attenuation of TNF-α by pregnancy-levels of oestrogen and progesterone has also been shown to further promote granuloma formation by decreasing TNF-induced-apoptosis of granuloma cells.15 The shielding effect of these hormones, along with their enhanced expression of angiogenic factors, implicates their importance in the pathogenesis of uncontrolled inflammation and may prove relevant in the pathogenesis of THS.3 15
In this patient, the chronic administration of combined oestrogen and progesterone on top of the immunomodulating effects of pregnancy could have precipitated her episodes of THS. To our knowledge, this is the first report of a THS relapse occurring during pregnancy following a chronic history of COC intake. This case adds to the growing evidence supporting the interplay between immune and hormonal factors and the disease pathogenesis of THS.
Learning points
Pregnancy and pregnancy-related hormones have been identified as potential triggers of Tolosa-Hunt syndrome (THS).
Immune response during pregnancy contributes to disease pathogenesis.
Oestrogen and progesterone may prove relevant in the pathogenesis of THS.
Contributors: BLCP: Research project: conception, organisation, execution. Manuscript preparation: writing of the first draft. KLO and ARC: Manuscript preparation: review and critique.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33462037 | 19,145,964 | 2021-01-18 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Death'. | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
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ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | BRENTUXIMAB VEDOTIN, DACARBAZINE, DOXORUBICIN HYDROCHLORIDE, VINBLASTINE | DrugsGivenReaction | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the administration route of drug 'BRENTUXIMAB VEDOTIN'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
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ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the administration route of drug 'DACARBAZINE'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
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ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the administration route of drug 'DOXORUBICIN HYDROCHLORIDE'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
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ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the administration route of drug 'VINBLASTINE'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
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ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the dosage of drug 'BRENTUXIMAB VEDOTIN'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
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ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | UNK, CYCLIC (ON DAYS 1 AND 15 OF EACH 28?DAY CYCLE FOR UP TO 6 CYCLES) | DrugDosageText | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the dosage of drug 'DACARBAZINE'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
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ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | UNK, CYCLIC (ON DAYS 1 AND 15 OF EACH 28?DAY CYCLE FOR UP TO 6 CYCLES) | DrugDosageText | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the dosage of drug 'DOXORUBICIN HYDROCHLORIDE'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
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ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | UNK, CYCLIC (ON DAYS 1 AND 15 OF EACH 28?DAY CYCLE FOR UP TO 6 CYCLES) | DrugDosageText | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the dosage of drug 'VINBLASTINE'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | UNK, CYCLIC (ON DAYS 1 AND 15 OF EACH 28?DAY CYCLE FOR UP TO 6 CYCLES) | DrugDosageText | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
What was the outcome of reaction 'Death'? | Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study.
Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
1 INTRODUCTION
Despite advances in recent years, advanced‐stage classical Hodgkin lymphoma (cHL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) relapses or becomes refractory in 25%–30% of patients.1, 2, 3 Bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) results in higher initial disease control in younger, fit patients but at the expense of significantly higher acute and late toxicity, secondary malignancies, and treatment‐related mortality.4, 5, 6 Patients with Stage IV disease have a relatively poor prognosis, with an overall survival (OS) rate of approximately 76% at 5 years. 7 The development of more‐effective yet tolerable treatment options for patients with advanced‐stage cHL, especially those with high‐risk characteristics, is warranted.
Brentuximab vedotin (BV) is a novel antibody‐drug conjugate targeting the CD30 antigen expressed on Hodgkin Reed–Sternberg cells. Across a range of trials, BV has been shown to induce durable remissions in patients with cHL who relapsed after autologous stem cell transplant. In the pivotal trial, BV treatment resulted in a complete response (CR) rate of 34% (95% confidence interval [CI], 25.2–44.4) and objective response rate of 75% (95% CI, 64.9–82.6) per independent review committee. 8 Notably, a subset of 15 patients from this study achieved complete remission and maintained their response for ≥5 years; of these, six patients received consolidative allogeneic stem cell transplant, and nine patients received no further therapy after completing BV treatment. 9 The use of BV as a consolidation treatment option for adult patients with cHL at high risk of relapse or progression following autologous hematopoietic stem cell transplant resulted in improved progression‐free survival (PFS) compared with placebo. 10 In a Phase 1 dose‐escalation study of BV in combination with AVD, 24 of 25 patients (96%) with newly diagnosed cHL achieved complete remission. 11 Based on these findings, a global, multicenter, open‐label, randomized, phase 3 clinical study, the ECHELON‐1 trial, was conducted to assess the efficacy and safety of a therapeutic combination of BV plus AVD (A + AVD) versus ABVD as first‐line therapy in advanced stage (III and IV) cHL. 12
At a median follow‐up of 24.6 months, primary analyses of ECHELON‐1 showed a 23% risk reduction for modified PFS (hazard ratio [HR] for progression, death, or modified progression event, 0.77; 95% CI, 0.60–0.98; p = 0.035) in patients receiving A + AVD, with 2‐year modified PFS rates of 82.1% (95% CI, 78.8%–85.0%) in patients receiving A + AVD and 77.2% (95% CI, 73.7%–80.4%) in those receiving ABVD. 12 At the primary analysis, 28 deaths had occurred with A + AVD and 39 with ABVD (HR for interim OS, 0.72; 95% CI, 0.44–1.17; p = 0.19). 12
This post hoc analysis includes the updated 3‐year efficacy and safety of A + AVD compared with ABVD (data cutoff, 15 October 2018; median follow‐up for PFS was 37.1 months) in a prespecified high‐risk patient subgroup presenting at baseline with Stage IV disease or an International Prognostic Score (IPS) of 4–7.
2 METHODS
2.1 Patient eligibility and study design
Full details of the ECHELON‐1 study (ClinicalTrials.gov identifier NCT01712490; EudraCT 2011‐005450‐60) have been published.12, 13 Briefly, we recruited patients aged ≥18 years with histologically confirmed cHL (Ann Arbor stage III or IV) who had not been previously treated with systemic chemotherapy or radiotherapy and had an Eastern Cooperative Oncology Group performance status of 0–2 (Figure S1).
Patients were randomized 1:1 to receive A + AVD or ABVD intravenously on Days 1 and 15 of each 28‐day cycle for up to six cycles, with stratification by IPS (0–1, 2–3, or 4–7) and region (Americas, Asia, or Europe).
ECHELON‐1 was conducted in accordance with regulatory requirements; the protocol was approved by the institutional review boards and ethics committees at each registered site. Written informed consent per the local ethics committee was mandatory before enrollment. This study was conducted according to the guideline of the International Conference on Harmonisation Good Clinical Practice.
2.2 Endpoints
The primary endpoint was modified PFS per an independent review facility (IRF), defined as the time to disease progression, death, or modified progression event (with the latter defined as evidence of non‐CR after completion of frontline therapy according to review by an independent committee, followed by subsequent anticancer therapy). 12 Non‐CR was defined by an end‐of‐therapy positron emission tomography (PET) scan with a Deauville five‐point scale score of 3–5. The key secondary endpoint was OS (time from date of randomization to date of death). These endpoints were specified in the primary analysis (data cutoff, 20 April 2017).
PFS per investigator for the intent‐to‐treat (ITT) population was a preplanned supportive analysis. At a median follow‐up of 37.1 months, we report extended follow‐up of PFS (defined as time to progression or death) per the investigator for patients with Stage IV disease or an IPS of 4–7. Following the primary analysis, the protocol did not require investigators to submit further information to the IRF.
2.3 Statistical analysis
Stratified log‐rank testing was used to compare modified PFS and OS between the two treatment arms as part of the primary analysis and key secondary analysis in the ITT population. Stratification factors included geographic region and IPS at baseline. HRs, along with 95% CIs, were estimated using a stratified Cox model, with treatment as the explanatory variable.
In the primary analysis, a broad number of prespecified subgroup analyses was performed, including region, extranodal site involvement, IPS, sex, disease stage, and age. 12 The present subgroup analyses for PFS used unstratified Cox models and unstratified log‐rank testing and included the following subgroups: stage (III vs. IV) and IPS (0–1 vs. 2–3 vs. 4–7).
Extended follow‐up of modified PFS per IRF was not feasible following the primary analysis because the protocol did not require investigators to submit further information to the IRF. Additional supportive analyses were performed to evaluate the treatment effects on PFS per the investigator and OS in these two prespecified groups. An unstratified Cox proportional hazards model was used to estimate HRs. All p values from subgroup analyses were based on unstratified log‐rank tests and are for descriptive purposes only, without multiplicity adjustment.
Safety was summarized for type, incidence, severity, seriousness, and relatedness of adverse events (AEs), as well as type, incidence, and severity of laboratory abnormalities. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 10.1 or higher. Laboratory values were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical analyses were performed using SAS version 9.1 or higher (SAS Institute).
3 RESULTS
A total of 1334 patients (ITT population) at 218 sites in 21 countries were randomly assigned to receive A + AVD (n = 664) or ABVD (n = 670). The data cutoff date for the present updated analysis was 15 October 2018, with a median follow‐up of 37.1 months and primary data from 20 April 2017 at a median follow‐up of 24.6 months. Overall, 64% of patients had Stage IV disease (64% in the A + AVD arm; 63% in the ABVD arm); 26% had an IPS of 4–7 (25% in the A + AVD arm; 27% in the ABVD arm). Baseline characteristics were balanced between the two treatment arms and are presented in Table 1 for patients with Stage IV disease (n = 846) and in Table S1 for those with an IPS of 4–7 (n = 347).
TABLE 1 Demographic and clinical characteristics of patients with Stage IV disease at baseline
Characteristic A + AVD (n = 425) ABVD (n = 421)
Male, n (%) 243 (57) 243 (58)
Age, years
Median 36 38
IQR 26.0–50.0 27.0–53.0
Age category, n (%)
<45 years 292 (69) 260 (62)
45–59 years 82 (19) 94 (22)
≥60 years 51 (12) 67 (16)
IPS risk factors, n (%)
0–1 55 (13) 43 (10)
2–3 225 (53) 227 (54)
4–7 145 (34) 151 (36)
Bone marrow involvement at diagnosis, n (%)
Yes 142 (33) 140 (33)
No 271 (64) 276 (66)
Unknown 12 (3) 5 (1)
ECOG performance status, n (%)
0 221 (52) 217 (52)
1 184 (43) 181 (43)
2 20 (5) 22 (5)
Patients with any B symptom, n (%) 276 (65) 256 (61)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG, Eastern Cooperative Oncology Group; IPS, International Prognostic Score , .
In patients with Stage IV disease at the time of the primary analysis, there was a 28.9% reduction in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.711; 95% CI, 0.529–0.956; p = 0.023). The modified PFS rate per IRF at 2 years was 82.0% (95% CI, 77.8%–85.5%) in the A + AVD arm compared with 75.3% (95% CI, 70.6%–79.3%) in the ABVD arm (Figure 1A ). An interim analysis of OS indicated that patients with Stage IV disease who received A + AVD had an almost 50% reduction in the risk of death (14/425 [3.3%]) compared with those who received ABVD (26/421 [6.2%]), with an HR of 0.507 (95% CI, 0.265–0.971; p = 0.037); the estimated 2‐year OS rate was 97.4% (95% CI, 95.3%–98.5%) in the A + AVD arm and 93.4% (95% CI, 90.3%–95.6%) in the ABVD arm (Figure 1B). In patients with an IPS of 4–7, a 44.2% reduction was observed in the risk of a modified PFS per IRF event in the A + AVD arm compared with the ABVD arm (HR, 0.558; 95% CI, 0.357–0.874; p = 0.010). The modified PFS per IRF rate at 2 years was 77.0% (95% CI, 69.5%–82.9%) in the A + AVD arm compared with 69.2% (95% CI, 61.5%–75.8%) in the ABVD arm (Figure 2A). Among patients with an IPS of 4–7, the interim analysis of OS showed a 48.1% reduction in risk of death in patients who received A + AVD (11/169 [6.5%]) compared with those who received ABVD (22/178 [12.4%]), with an HR of 0.519 (95% CI, 0.252–1.070; p = 0.070; Figure 2B).
FIGURE 1 Kaplan–Meier estimates of (A) modified PFS per the IRF and (B) OS by treatment arm among patients with Stage IV disease at primary analysis (data cutoff, 20 April 2017). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; IRF, independent review facility; OS, overall survival; PFS, progression‐free survival
FIGURE 2 Survival analyses in patients with an IPS of 4–7 at baseline by treatment arm at primary analysis (data cutoff, 20 April 2017). Kaplan–Meier estimates of (A) PFS per the INV, and (B) OS. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; OS, overall survival; PFS, progression‐free survival
The benefit of A + AVD versus ABVD was maintained in an analysis of PFS per investigator with median follow‐up of 3 years (HR, 0.70; 95% CI, 0.55–0.90; p = 0.005). Patients with Stage IV disease also benefited from treatment with A + AVD versus ABVD (HR, 0.723; 95% CI, 0.537–0.973; p = 0.032) with a 3‐year PFS rate of 81.8% (95% CI, 77.6%–85.3%) in the A + AVD arm and 74.9% (95% CI, 70.2%–78.9%) in the ABVD arm (a difference of 6.9%; Figure 3).
FIGURE 3 Updated survival analyses in patients with Stage IV disease by treatment arm (data cutoff, 15 October 2018). Kaplan–Meier estimates of PFS per the INV. Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
Patients with Stage IV disease experienced benefit with A + AVD across the majority of subgroups that were predefined for the ITT population in ECHELON‐1 (Figure 4). Notably, the PFS benefit per investigator at 3 years with A + AVD over ABVD was maintained in both younger (<60 years) and older (≥60 years) patients (HR, 0.760; 95% CI, 0.542–1.067 for patients aged <60 years; HR, 0.685; 95% CI, 0.367–1.278 for patients aged ≥60 years). In addition, the PFS benefit per investigator at 3 years with A + AVD over ABVD was noted in both PET2‐negative patients (A + AVD n = 379; ABVD n = 358) and ‐positive patients (A + AVD n = 34; ABVD n = 42) with Stage IV disease (HR, 0.732; 95% CI, 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients).
FIGURE 4 Forest plot of hazard ratios for PFS per INV at 3 years for subgroups of patients with baseline Stage IV Hodgkin lymphoma (data cutoff, 15 October 2018). INV, investigator; PFS, progression‐free survival
Patients with an IPS of 4–7 had results consistent with those in patients with Stage IV disease. The PFS per investigator at 3 years showed an improvement in the A + AVD arm compared with the ABVD arm, with an HR of 0.588 (95% CI, 0.386–0.894; p = 0.012; Figure 5). The 3‐year PFS rate in patients with an IPS of 4–7 was 79.6% (95% CI, 72.4%–85.1%) in the A + AVD arm and 65.7% (95% CI, 57.8%–72.4%) in the ABVD arm. The PFS benefit per investigator at 3 years with A + AVD over ABVD were noted in both PET2‐negative patients (A + AVD n = 144; ABVD n = 148) and ‐positive patients (A + AVD n = 16; ABVD n = 19) with an IPS of 4–7 (HR, 0.545; 95% CI 0.331–0.898 for PET2‐negative; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
FIGURE 5 Kaplan–Meier estimates of PFS per the INV by treatment arm at 3 years for patients with IPS of 4–7 (data cutoff, 15 October 2018). Hazard ratios, 95% CIs, and p values from log‐rank tests are presented; circles indicate censored data. A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; CI, confidence interval; INV, investigator; IPS, International Prognostic Score; PFS, progression‐free survival
3.1 Safety
Safety data are from the primary analysis (data cutoff date, 20 April 2017; median follow‐up was 24.6 months), with the exception of peripheral neuropathy (PN) and secondary malignancy data, which had a median follow‐up of 37.1 months (data cutoff, 15 October 2018). During the study, most patients with Stage IV disease experienced ≥1 treatment‐related AE, regardless of treatment (Table 2). Safety results in patients with Stage IV disease and IPS of 4–7 were consistent with safety results reported in the overall population and did not change with longer observation. 12 Among patients with Stage IV disease, drug‐related AEs occurred in 96% in the A + AVD arm and 93% in the ABVD arm. Patients with Stage IV disease receiving A + AVD experienced more grade ≥3 treatment‐emergent AEs (83% vs. 67%), grade ≥3 drug‐related AEs (79% vs. 61%), and serious AEs (40% vs. 28%) than those receiving ABVD, respectively, but fewer of those receiving A + AVD died within 30 days of the last dose of frontline therapy (5 vs. 8 patients, respectively; Table 2). Patients with an IPS of 4–7 at baseline had similar safety profiles to those with Stage IV disease and the overall population (Table S2).
TABLE 2 AEs reported in patients with Stage IV Hodgkin lymphoma
AE, n (%) A + AVD (n = 424) ABVD (n = 413)
Any AE 416 (98) 403 (98)
Drug‐related AE 408 (96) 383 (93)
Grade ≥3 AE 352 (83) 278 (67)
Drug‐related grade ≥3 AE 336 (79) 250 (61)
Serious AE 170 (40) 114 (28)
Drug‐related serious AE 140 (33) 83 (20)
AE resulting in study drug or dose discontinuation 44 (10) 66 (16)
AE resulting in dose modification a 268 (63) 184 (45)
Dose held 26 (6) 22 (5)
Dose interrupted 12 (3) 20 (5)
Dose reduced 121 (29) 41 (10)
Dose delayed 204 (48) 138 (33)
On‐study death 5 (1) 8 (2)
Death due to drug‐related AE 5 (1) 5 (1)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AE, adverse event.
a Table is based on the number of patients, and one patient might have multiple AEs.
Consistent with results in the overall population, more patients with Stage IV disease in the A + AVD arm experienced any‐grade treatment‐emergent PN (67% vs. 40%), neutropenia (71% vs. 55%), and febrile neutropenia (19% vs. 8%) than those in the ABVD arm.
More patients with an IPS of 4–7 in the A + AVD arm experienced PN (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%) than those in the ABVD arm.
PN was managed with dose modification and was generally reversible. At a data cutoff of 15 October 2018 (median follow‐up, 36.1 months after end of treatment), PN resolution and improvement rates had continued to increase in patients who were treated with A + AVD or ABVD. At last follow‐up, the majority of patients with Stage IV disease in the A + AVD arm (80%) and ABVD arm (85%) had experienced resolution of or improvement in PN (Table 3); the proportion of patients with resolution of or improvement in PN was similar in the groups of patients with an IPS of 4–7. Consistent with reports for the overall population, the rates of neutropenia and febrile neutropenia in these subgroups were reduced in patients who received primary granulocyte colony‐stimulating factor (G‐CSF) prophylaxis (Table S3). The use of primary G‐CSF prophylaxis is recommended for all patients receiving the A + AVD combination. 11 In the ABVD arm, pulmonary toxicity by standardized MedDRA queries were reported in 27 of 413 patients (7%) with Stage IV disease and in 5% of patients with an IPS of 4–7 (Table S4). In the A + AVD arm, pulmonary toxicity events by standardized MedDRA queries were reported in eight of 424 patients (2%) with Stage IV disease and two of 168 patients (1%) with an IPS of 4–7. Among patients with Stage IV disease, deaths due to pulmonary toxicity were reported in three of 413 patients who received ABVD and no patients who received A + AVD.
TABLE 3 PN resolution in Stage IV patients (median follow‐up, 36.1 months postend of treatment)
Outcome of PN events at last follow‐up, n (%) A + AVD (n = 283) ABVD (n = 165) Total (N = 448)
Maximum severity grades, n (%)
1 58 (20) 27 (16) 85 (19)
2 30 (11) 14 (8) 44 (10)
3 9 (3) 3 (2) 12 (3)
4 1 (<1) 0 1 (<1)
Resolution a of or improvement b in PN events 225 (80) 140 (85) 365 (81)
Resolution a of all PN events 185 (65) 121 (73) 306 (68)
Improvement b in PN events 40 (14) 19 (12) 59 (13)
No resolution of or improvement in any PN events 58 (20) 25 (15) 83 (19)
Abbreviations: A + AVD, brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; PN, peripheral neuropathy.
a Defined as event outcome of “resolved” or “resolved with sequelae.”
b Resolution implies improvement. In addition, for events that were not resolved, improvement was defined as decrease by ≥1 grade from the worst grade, with no higher grade thereafter.
In the overall ECHELON‐1 study population at a median follow‐up of approximately 3 years, 34 patients developed secondary malignancies, including 14 in the A + AVD arm (2.3%) and 20 in the ABVD arm (3%). A total of three patients developed secondary AML— two in the A + AVD arm and one in the ABVD arm. One patient in the ABVD arm and none in the A + AVD arm developed secondary myelodysplastic syndrome. In the A + AVD arm, solid malignancies occurred in five patients and other hematologic malignancies in five patients. In the ABVD arm, solid malignancies occurred in six patients and hematologic malignancies in seven patients. In patients with Stage IV disease, secondary malignancies occurred in eleven of 425 patients (2.6%) in the A + AVD arm (four solid and seven hematologic malignancies) and 14 of 421 patients (3.3%) in the ABVD arm (five solid and nine hematologic malignancies). Among patients with an IPS of 4–7, secondary malignancies occurred in five of 168 (3.0%; two solid and three hematologic malignancies) and 10 of 175 (5.7%; three solid and seven hematologic malignancies) patients receiving A + AVD and ABVD, respectively.
4 DISCUSSION
Although cHL has a high 5‐year failure‐free survival rate of more than 80% in all disease stages, patients with Stage IV disease treated with ABVD have a comparatively lower 5‐year failure‐free survival rate (76%).1, 7, 14, 15 Similarly, patients with an IPS of 4–7 at diagnosis often have a poor prognosis. 16
The ECHELON‐1 trial showed a statistically significant improvement in modified PFS by the IRF and additional improvement in PFS per the investigator in patients with stage III or IV disease who received A + AVD compared with those who received ABVD. 12 In this analysis, we focused on patients at a high risk of treatment failure as indicated by baseline disease characteristics, including Stage IV disease and an IPS of 4–7. This subgroup analysis included additional efficacy (2‐year PFS, OS) and safety results and updated 3‐year PFS in the context of the ITT population. The results demonstrated that the value of adding BV to first‐line treatment for patients with advanced HL is greater in high‐risk patients and demonstrated that high‐risk features may help all clinicians who treat advanced stage HL to predict poor treatment outcomes with standard ABVD, which can be partially overcome with the addition of BV.
At the primary analysis, an improvement was observed in the risk of a modified PFS event in both high‐risk patients who received A + AVD versus those who received ABVD. Furthermore, an improvement in OS was noted in patients with Stage IV disease in favor of A + AVD. The results of the primary analysis strongly supported the superiority of A + AVD over ABVD in patients with Stage IV disease as well as those with a high IPS. The safety profile of A + AVD observed in the two high‐risk subgroups was comparable to that observed in the overall safety population, and no new safety signals were identified. Importantly, patients with high‐risk cHL did not experience an increased incidence or severity of AEs, consistent with what was observed in the overall safety population.
Since the primary analysis, this patient population has also been assessed at a median follow‐up of approximately 3 years. A previously published analysis of the ITT population at 3 years demonstrated the durable benefit of A + AVD versus ABVD in patients independent of age, disease stage, or risk‐factor score without requiring change of therapy or exposure to bleomycin. 13 In this analysis of patients with Stage IV disease, an analysis of PFS by investigator demonstrated an improvement that was maintained at 3 years with A + AVD versus ABVD, with a reduction in the risk of a PFS event of 28% (HR, 0.723; 95% CI, 0.537–0.973). In addition, benefit based on PFS per investigator assessment in patients with an IPS of 4–7 was also maintained at a median follow‐up of 3 years (HR, 0.588; 95% CI, 0.386–0.894). 13 These updated results are consistent with the results of the primary analysis and further support the use of A + AVD as a meaningful treatment option for patients with high‐risk cHL.
Upon treatment outcome being stratified in patients with Stage IV disease according to PET2 status, both PET2‐negative and PET2‐positive cohorts had a better outcome in the experimental versus the standard arm (HR, 0.732; 95% CI 0.520–1.031 for PET2‐negative patients; HR, 0.727; 95% CI, 0.366–1.445 for PET2‐positive patients). PET‐2‐negative and PET‐2‐positive cohorts with IPS 4–7 also had a better outcome in the experimental versus the standard arms (HR, 0.545; 95% CI, 0.331–0.898 in PET2‐negative patients; HR, 0.510; 95% CI, 0.190–1.365 in PET2‐positive patients).
In recent years, multiple clinical trials, including SWOG S0816, RATHL, and GITIL/FIL HD 0607, have focused on improving outcomes in patients with advanced stage cHL by managing patients who are initiated on ABVD and have a positive PET2 result with escalation of therapy to BEACOPPesc.17, 18, 19 The comparison of ECHELON‐1 with studies of BEACOPPesc or PET response–adapted BEACOPPesc‐based regimens is difficult because of important differences in inclusion criteria (different proportions of patients with stage II disease, different age ranges), PET interpretation rules, and study endpoints (PFS vs. modified PFS). In addition, although the use of BEACOPPesc has shown superior 3‐ and 5‐year PFS compared with standard ABVD in PET2‐positive patients, it comes at the cost of increased short‐ and long‐term toxicities, including infertility and secondary malignancies. 4 In the primary SWOG S0816 study, secondary malignancies were observed in 6% of PET2‐positive patients receiving BEACOPPesc or BEACOPP‐14 with 3.3 years of follow‐up, and the rate increased to 14% with 5.9 years of follow‐up. 17 In the RATHL and HD0607 trials, the rate of secondary malignancies was lower, but the follow‐up in these two studies was shorter.16, 17 In ECHELON‐1, the rate of secondary malignancies on the A + AVD arm was 2.8% (Stage IV, 2.6%; IPS of 4–7, 3.3%) and 3% in the ABVD arm (Stage IV, 3.3%; IPS of 4–7, 5.7%). Although follow‐up is ongoing, these secondary malignancy data from ECHELON‐1 suggest that the rate with A + AVD did not exceed that with ABVD; hence, A + AVD could provide an effective alternative to BEACOPPesc that could potentially spare patients the associated long‐term toxicities.
One notable limitation to these analyses is that although these subgroups were prespecified, they were not alpha‐controlled; thus, p values cannot be adjusted for inferential purposes. Additionally, there is a potential for a close interaction between subgroups to confound the observed treatment benefit. For example, the presence of Stage IV disease is one of the seven risk factors included in the IPS, resulting in a higher chance that a patient will be in both subgroups. 20 Overlapping of other risk factors, such as extranodal involvement, advanced age, or subtype, may also exist. It is therefore difficult to ascertain the exact attribute or attributes that determine greater benefit with A + AVD.
In ECHELON‐1, A + AVD provided clinically meaningful improvements in modified PFS, with an acceptable safety profile, supporting a favorable benefit‐risk balance in the first‐line treatment of adult patients with cHL, including those with Stage IV disease or an IPS of 4–7. With continued follow‐up of PFS per investigator, a consistent benefit with A + AVD over ABVD has been observed across prespecified subgroups, including patients with high‐risk characteristics.
CONFLICT OF INTERESTS
Martin Hutchings received research funding and consulting fees from Takeda, Roche, and Celgene. John Radford received consulting fees from ADC Therapeutics, Takeda, Bristol‐Myers Squibb, and Novartis. Stephen M. Ansell received research funding from Takeda, Seattle Genetics, Bristol‐Myers Squibb, Affimed, Regeneron, LAM Therapeutics, and Trillium. Anna Sureda participated in educational activities for Takeda, BMS, Roche, Gilead, and Novartis and received honoraria from Takeda, Celgene, Janssen, Gilead, and Novartis. Joseph M. Connors received honoraria from Seattle Genetics and Takeda. Hirohiko Shibayama received grants and honoraria from Celgene, Daiichi Sankyo, Eisai, Janssen, Nippon Shinyaku, Ono, Novartis, and Takeda; received grants from Astellas, Teijin, MSD, Shionogi, Sumitomo Dainippon, Taiho, and Mundipharma; and received honoraria from Chugai, Kyowa Kirin, Otsuka, AstraZeneca, AbbVie, Fujimoto, Sanofi, Bristol‐Myers Squibb, and Pfizer. Jeremy S. Abramson received research funding and consulting fees from Seattle Genetics. Neil S. Chua received an honorarium from Seattle Genetics. Jonathan W. Friedberg received research funding from Seattle Genetics, consulting fees from Bayer and Acerta, and travel expenses from Roche. Ann Steward LaCasce received consulting fees from Seattle Genetics. Gerald Engley is an employee of Seattle Genetics. Keenan Fenton is an employee of Seattle Genetics and holds stock or stock options in Seattle Genetics. Hina Jolin is an employee of Takeda. Rachael Liu is an employee of Takeda. Ashish Gautam is an employee of Takeda. Andrea Gallamini received consulting fees from Takeda. The other authors declare that there are no conflicts of interests.
AUTHOR CONTRIBUTIONS
Martin Hutchings contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript. John Radford contributed to manuscript writing and final approval of the manuscript. Stephen M. Ansell contributed to the study design, data collection, data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Árpád Illés contributed to manuscript writing and final approval of the manuscript. Anna Sureda contributed to data analysis, data interpretation, manuscript writing, and final approval of the manuscript. Joseph M. Connors served on the trial committee and contributed to the study design, data collection, data interpretation, manuscript writing, and final approval of the manuscript. Alice Sýkorová contributed to manuscript writing and final approval of the manuscript. Hirohiko Shibayama contributed to data collection and final approval of the manuscript. Jeremy S. Abramson contributed to manuscript writing and final approval of the manuscript. Neil S. Chua contributed to patient enrollment and oversight, data collection, data analysis, and data interpretation. Jonathan W. Friedberg contributed to patient enrollment and oversight, data collection, data analysis, data interpretation, and final approval of the manuscript. Jan Kořen contributed to manuscript writing and final approval of the manuscript. Ann Steward LaCasce contributed to manuscript writing and final approval of the manuscript. Lysiane Molina contributed to manuscript writing and final approval of the manuscript. Gerald Engley contributed to data collection and manuscript writing. Keenan Fenton contributed to data analysis, data interpretation, and manuscript writing. Hina Jolin contributed to protocol writing, data collection, data analysis, and data interpretation. Rachael Liu contributed to data collection, data analysis, and data interpretation. Ashish Gautam contributed to data collection, data analysis, and data interpretation. Andrea Gallamini contributed to the study design, patient accrual, data collection, data interpretation, data analysis, manuscript writing, critical revision of the manuscript, and final approval of the manuscript.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1002/hon.2838.
Supporting information
Supplementary Material
Click here for additional data file.
ACKNOWLEDGMENTS
The authors would like to thank the patients who participated in this trial and their relatives, as well as the investigators and staff at all ECHELON‐1 clinical sites; the members of the independent data and safety monitoring committee and the independent review committee; Jeanenne Chung, Vijay Maharaj, Tae M. Hotniansky, and Andy Chi of Millennium Pharmaceuticals for their contributions to the conception and execution of the ECHELON‐1 trial; and Brad Imwalle, PhD, MBA, and Jackie Stone, PhD, of SciMentum, Inc., for writing support during the development of the manuscript, which was supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. | Fatal | ReactionOutcome | CC BY-NC-ND | 33462822 | 18,887,415 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.
A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.
In recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.
Case Report
An immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.
An uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.
Figure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble
Patient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.
Figure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)
Discussion
Post DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.
The second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]
Corneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]
Conclusion
A high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | METHYLPREDNISOLONE ACETATE, MOXIFLOXACIN HYDROCHLORIDE, PREDNISOLONE ACETATE | DrugsGivenReaction | CC BY-NC-SA | 33463607 | 19,436,298 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ophthalmic herpes simplex'. | Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.
A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.
In recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.
Case Report
An immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.
An uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.
Figure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble
Patient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.
Figure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)
Discussion
Post DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.
The second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]
Corneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]
Conclusion
A high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | METHYLPREDNISOLONE ACETATE, MOXIFLOXACIN HYDROCHLORIDE, PREDNISOLONE ACETATE | DrugsGivenReaction | CC BY-NC-SA | 33463607 | 19,436,298 | 2021-02 |
What was the administration route of drug 'METHYLPREDNISOLONE ACETATE'? | Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.
A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.
In recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.
Case Report
An immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.
An uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.
Figure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble
Patient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.
Figure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)
Discussion
Post DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.
The second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]
Corneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]
Conclusion
A high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-SA | 33463607 | 19,436,298 | 2021-02 |
What was the administration route of drug 'PREDNISOLONE ACETATE'? | Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.
A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.
In recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.
Case Report
An immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.
An uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.
Figure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble
Patient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.
Figure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)
Discussion
Post DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.
The second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]
Corneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]
Conclusion
A high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | Topical | DrugAdministrationRoute | CC BY-NC-SA | 33463607 | 19,436,298 | 2021-02 |
What was the dosage of drug 'METHYLPREDNISOLONE ACETATE'? | Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.
A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.
In recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.
Case Report
An immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.
An uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.
Figure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble
Patient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.
Figure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)
Discussion
Post DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.
The second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]
Corneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]
Conclusion
A high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | 1 G, DAILY | DrugDosageText | CC BY-NC-SA | 33463607 | 19,436,298 | 2021-02 |
What was the dosage of drug 'MOXIFLOXACIN HYDROCHLORIDE'? | Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.
A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.
In recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.
Case Report
An immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.
An uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.
Figure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble
Patient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.
Figure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)
Discussion
Post DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.
The second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]
Corneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]
Conclusion
A high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | 5 MG/ML, 3X/DAY | DrugDosageText | CC BY-NC-SA | 33463607 | 19,436,298 | 2021-02 |
What was the outcome of reaction 'Drug ineffective'? | Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.
A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.
In recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.
Case Report
An immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.
An uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.
Figure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble
Patient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.
Figure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)
Discussion
Post DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.
The second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]
Corneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]
Conclusion
A high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC-SA | 33463607 | 19,436,298 | 2021-02 |
What was the outcome of reaction 'Ophthalmic herpes simplex'? | Presumed herpes simplex virus endotheliitis following ultra-thin Descemet's stripping automated endothelial keratoplasty.
A 78.year.old male underwent ultra.thin DSAEK for PBK (OS) and achieved BCVA 6/12 at 9 months. The patient developed allograft rejection 10 months postoperatively and was treated with IV methyl prednisolone, systemic, and topical steroids. The patient then improved and achieved 6/18 BCVA at 8 weeks. Topical prednisolone 1% twice daily was continued. Six weeks later, the patient developed fever and diminished vision and had high IOP, corneal edema, and keratic precipitates on endothelium. Considering it to as second episode of graft rejection, IV methyl prednisolone and topical steroids were given. Seeing no response, presumed HSV endotheliitis was considered as diagnosis and treated with steroids, oral acyclovir. The patient improved and achieved BCVA 6/24 with no subsequent recurrence during 11 months follow.up.
In recent years endothelial keratoplasty (EK) has emerged as a standard of care for the management of pseudophakic corneal edema (PBK). Both Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) have advantages over penetrating keratoplasty (PKP) including, non-compromised wound strength, elimination of suture related complications, less post-surgery astigmatism, and early visual rehabilitation.[1] In addition lower incidence of allograft rejection following DSAEK is a major advantage.[1] From clinical standpoint, it is important to differentiate allograft rejection from Herpes simplex virus (HSV) endotheliitis as the treatment is different and antiviral prophylaxis to prevent recurrence is needed.[2] We report an unusual case, who developed HSV endotheliitis after successful treatment of allograft rejection following ultrathin DSAEK performed for PBK.
Case Report
An immunocompetent 78-years-old male presented with pain, redness, watering and diminished vision (DV) in OS, 7 months following cataract surgery. Patient did not reveal any history of recurrent redness. His BCVA in the OD was 6/6 and 6/60 OS. Intra ocular pressures in OD and OS were 17 and 16 mm Hg, respectively. Slit lamp biomicroscopy revealed clear cornea and pseudophakia OD and marked corneal edema OS. There were no keratic precipitates (KPs), no synechiae and well centered PCIOL in either eye. Retina examination did not reveal any abnormality OD. B scan of the OS was normal. Diagnosis of PBK was considered and ultrathin DSAEK in OS was planned.
An uneventful ultrathin-DSAEK was performed on 28th Dec 2017. A clear corneal incision with 2.8 mm disposable keratome was made. Two side ports were prepared. Descemets membrane was stripped off using a reverse sinskey hook. Donor lenticule 8.0 mm diameter was punched out from the pre-cut donor cornea. Donor cornea had 2870/mm2 endothelial cell density and 92 microns thick donor lenticule. Donor lenticule was loaded into the Endosaver (SightLife surgical, Winston-Salem, NC 27101 USA) and was delivered into the anterior chamber. An air bubble was placed in the anterior chamber and the lenticule was centered. Patient was made to lie down for 20 minutes. After 1 hour 20% of air was removed. Patient was put on moxifloxacin 0.5% (Vigamox 5 mg/ml; Alcon Laboratories, USA, Inc.), prednisolone accetate 1% suspension (Pred Forte, 10 mg/ml Allergan USA, Inc.) and cyclopentolate hydrochloride 1% (Cyclate 10 mg/ml ZydusCadila Healthcare Ltd, India) each thrice daily. Post-operative period was uneventful [Fig. 1. Patient achieved BCVA 6/24 at 1 month and further improved to 6/18 (-1.25/-2.50 × 800) at 3 months. IOP was normal. Topical steroid was tapered to prednidolone 1% twice daily. Patient achieved BCVA 6/12 at 9 months follow-up.
Figure 1 DSAEK 72 hour post op, Clear cornea, well centered and firmly attached donor lenticule with partially absorbed air bubble
Patient developed sudden DV in OS 10 months after surgery. He had corneal edema and medium sized KP's on donor lenticule and was diagnosed as allograft rejection [Fig. 2a]. He was given I/V methyl prednisolone (IVMP) I gm daily for 3 days and topical prednisolone acetate 1% every 1 hour. Patient improved, steroids were tapered and achieved BCVA 6/18 at 8 weeks [Fig. 2b]. Topical prednisolone 1% twice daily was continued. Six weeks later patient had fever and again developed DV in OS. His IOP in OD and OS were 18 and 29 mm Hg. Slit lamp biomicroscopy revealed corneal edema, KP's on donor lenticule [Fig. 2c]. Considering second episode of graft rejection patient was given I/V methyl prednisolone 1 gm daily for three days in addition to topical prednisolone 1% 1 hourly. Patient did not show any response at 1 week. Then diagnosis of presumed HSV endotheliitis was considered and was given oral acyclovir 400 mg 5 times a day in addition to steroids. Patient improved and achieved 6/24 at 6 weeks [Fig. 2d]. Topical prednisolone 1% was gradually reduced to twice daily. Patient was kept on acyclovir 400 mg twice daily and did not develop any recurrence during 11 months follow-up.
Figure 2 (a) Corneal edema and KPs on donor lenticule (Graft rejection post DSAEK, active) (b) Clear cornea and old KPs (Graft rejection, healed at 8 weeks) (c) Corneal edema with KPs on donor lenticule (HSV endotheliitis) (d) Clear cornea with few old KPs (HSV endotheliitis healed. Positive response to Acyclovir and Steroid)
Discussion
Post DSAEK allograft rejection has been reported in 0.6% patients. HSV-1 DNA has been isolated from 2 of 51 (4.0%) failed DSAEK grafts.[3] Preoperative diagnosis was HSV endotheliitis in the first and failed PKP for keratoconus in second.[3] HSV endotheliitis after successful treatment of graft rejection following DSAEK for PBK has not been reported. Clinical differentiation between the two is necessary as HSV endotheliitis needs acyclovir during treatment and prophylaxis.
The second episode made us suspicious whether we are dealing with graft rejection or HSV endotheliitis. Episode of fever before onset of DV is characteristic of HSV recurrence. Patient developed recurrence of inflammation, while he was still on topical steroids. Fresh KPs on the graft and raised IOP indicated more of HSV endotheliitis. It is possible that due to prior topical steroid instillation KPs on host cornea were not seen. Three consecutive doses of IVMP as in optic neuritis, were given to achieve maximum anti-inflammatory response and to reset the aberrant immune response.[45] Patient did not respond to steroids alone, but responded to combination of steroids and oral acyclovir. Patient did not develop any recurrence during 11 months of follow-up while on acyclovir prophylaxis. Clinical presentation, response to oral acyclovir, and no recurrence during acyclovir prophylaxis confirm the diagnosis of presumed HSV endotheliitis.[2]
Corneal endotheliitis may also occur due to varicella zoster virus (VZV) and cytomegalo virus (CMV).[6] Post DSAEK endotheliitis patients not responding to combined acyclovir and corticosteroids, have been advocated confocal microscopy and aqueous tap for viral DNA PCR.[7] Coin shaped KP's on confocal microscopy indicate CMV endotheliitis and positive PCR test is confirmatory.[89] For CMV endotheliitis treatment gancyclovir is preferred.[10]
Conclusion
A high index of suspicion is needed in cases with post DSAEK recurrent endotheliitis and suboptimal response to steroids. An aqueous tap for viral PCR may be performed in such a scenario for an early diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest. | Recovered | ReactionOutcome | CC BY-NC-SA | 33463607 | 19,436,298 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Antinuclear antibody increased'. | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, METHYLPREDNISOLONE, MYCOPHENOLIC ACID, TACROLIMUS | DrugsGivenReaction | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Butterfly rash'. | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, METHYLPREDNISOLONE, MYCOPHENOLIC ACID, TACROLIMUS | DrugsGivenReaction | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Osteonecrosis'. | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, METHYLPREDNISOLONE, MYCOPHENOLIC ACID, TACROLIMUS | DrugsGivenReaction | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Red blood cell sedimentation rate increased'. | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | CYCLOPHOSPHAMIDE, HYDROXYCHLOROQUINE, METHYLPREDNISOLONE, MYCOPHENOLIC ACID, TACROLIMUS | DrugsGivenReaction | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
What was the administration route of drug 'CYCLOPHOSPHAMIDE'? | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
What was the dosage of drug 'HYDROXYCHLOROQUINE'? | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | .2 g (grams). | DrugDosage | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
What was the dosage of drug 'MYCOPHENOLIC ACID'? | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | .75 g (grams). | DrugDosage | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
What was the dosage of drug 'TACROLIMUS'? | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | 3 mg (milligrams). | DrugDosage | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
What was the outcome of reaction 'Antinuclear antibody increased'? | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | Recovered | ReactionOutcome | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
What was the outcome of reaction 'Butterfly rash'? | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | Recovered | ReactionOutcome | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
What was the outcome of reaction 'Osteonecrosis'? | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | Recovered | ReactionOutcome | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
What was the outcome of reaction 'Red blood cell sedimentation rate increased'? | Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report.
BACKGROUND
Osteonecrosis (ON) is a devastating illness that leads to bone ischemia and potential joint destruction. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, with multi-system involvement which is closely associated with occurrence of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is extremely rare in juvenile subjects.
A 13.3-year-old female SLE patient was admitted to hospital 20 months following the SLE diagnosis because of a sudden aggravation of sore knees. She suffered from double knee joint pain and her left knee joint showed typical signs of inflammation including redness, swelling, heat, and pain.
The SLE patient was diagnosed with multifocal ON of her knee joint based on magnetic resonance imaging findings of bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia.
METHODS
The patient received high-dose methylprednisolone and intravenous cyclophosphamide pulse therapies for controlling active lupus and nephritis. Oral calcitriol and dipyridamole were administered to alleviate knee pain and inhibit thrombi formation, thereby suppressing ON progress.
RESULTS
Three weeks following the treatment, the swelling in patient's left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45minutes to 90minutes per day. Nearly 5 weeks later, the pain in bilateral knee joints disappeared and the patient could walk without difficulties.
CONCLUSIONS
This patient is the youngest SLE patient who developed multifocal ON based on the reported literature. It suggests that ON can occur in young SLE patients. A combination of internal and external risk factors can promote the development of ON. The balanced approach to the application of corticosteroids and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem that deserves further exploration.
1 Introduction
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with multi-system involvement, and unclear pathogenesis. Osteonecrosis (ON) is one of the common complications of SLE that manifests with joint pain, bone destruction, and walking difficulties. Prevalence of ON in SLE ranges from 3% to 44%.[1–4] Compared with adolescent and adult SLE patients, pediatric patients have significantly lower rates of ON.[2] The most frequently affected site in ON is the femoral head, followed by knees, hips, shoulders, and ankles. Elbow, wrist, and foot involvement have also been reported, but rare in SLE patients.[4] Multifocal ON, which has been defined as occurrence in 3 or more anatomic sites have osteonecrosis lesions, but is not frequent in SLE and has a morbidity of approximately 3%.[5] Magnetic resonance imaging (MRI) is regarded as a gold standard in the diagnosis of ON and it helps to detect both symptomatic and silent ON.[6] Several mechanisms participate in the formation of ON in SLE. Fat accumulation in the bone increases intramedullary pressure and impairs endothelial cells, resulting in capillary rarefaction, disturbance of coagulation-fibrinolysis system, and thrombi formation.[7,8] Meanwhile, decreased expression of vascular endothelial growth factor (VEGF) suppresses angiogenesis and aggravates interruption of blood supply and lack of oxygen in bone tissues.[8,9] In addition, increased apoptosis of osteoblasts and osteocytes, prolonged lifespan of osteoclasts, and destroyed bone repair system also play an important role in the development of ON.[10]
2 Case presentation
A 11.6-year-old Chinese girl was diagnosed with SLE in October 2017. Initially, she presented with fever, malar butterfly erythema, vasculitis, hemolytic anemia, heavy proteinuria, C3 and C4 hypocomplementemia, hepatic function damage, positive direct Coombs’ test, positive antinuclear antibodies (ANA), anti-dsDNA, anti-Sm, anti-SSA, and anti-SSB antibodies. During the first 2 months after diagnosis (1st to 3th hospitalizations), she received high-dose methylprednisolone pulse therapies (0.5 g daily for 2 days) twice and intravenous cyclophosphamide pulse therapies (400 mg every time for a cumulative dose of 1.2 g) thrice. Moreover, hydroxychloroquine (0.2 g daily), mycophenolate mofetil (0.75 g daily), and tacrolimus (3 mg daily) were administered during the subsequent treatments. The patient experienced a relapse with appearance of a new malar butterfly erythema and erythrocyte sedimentation rate (ESR) increased to >140 mm/hour, accompanied by ANA titer increase to 1:1000 at the 4th hospitalization (Table 1). Through adjustments of corticosteriods dosage and combination of immunosuppressors, the patient's active lupus was gradually controlled and her clinical manifestations improved. At the 7th hospitalization, her ANA titer, ESR, 24-hour urinary protein quantity, and system lupus erythematosus disease activity index (SLEDAI) all significantly decreased and complement C3 significantly increased (Table 1).
Table 1 Clinical features of the systemic lupus erythematosus patient with osteonecrosis during every hospitalization.
Hospitalizations ANA titer Anti-dsDNA ESR (mm/h) 24 h urinary protein (mg) Complement C3 (g/L) SLEDAI
1 +1:100 Positive 92 8603.1 0.22 19
2 +1:320 Negative 105 2417.8 0.37 15
3 +1:320 Negative 112 3931.7 0.32 15
4 +1:1000 Positive >140 1590.0 0.30 19
5 +1:1000 Positive >140 1315.1 0.35 17
6 +1:320 Positive 42 2967.0 0.39 16
7 +1:100 Positive 21 801.0 0.76 14
8 +1:640 Positive 29 2081.1 0.64 18
9 +1:640 Positive 54 1011.3 0.91 16
10 +1:640 Positive 58 1602.7 0.74 14
ANA = antinuclear antibodies, ESR = erythrocyte sedimentation rate, SLEDAI = system lupus erythematosus disease activity index. The table displayed clinical features including ANA, anti-dsDNA, ESR, 24 h urinary protein, complement C3, and SLEDAI of the systemic lupus erythematosus patient with osteonecrosis at every hospitalization.
Nevertheless, in July 2019, when the patient was 13.3 years old (20 months later after diagnosis), she was admitted to the hospital (8th hospitalization) because of a sudden aggravation of sore knees. She suffered from bilateral knee joint pain and her left knee joint manifested typical infection reactions including redness, swelling, heat, and pain. Knee joint MRI screening presented bone destruction and osteoproliferation at the bilateral distal femur and proximal tibia, which implied symptomatic osteonecrosis (Fig. 1). In addition, increased ANA titer, 24-hour urinary protein quantity, and SLEDAI indicated a relapse. Her renal pathologic diagnosis was class IV diffuse proliferative lupus nephritis [IV-G(A/C)] through a percutaneous renal biopsy (Fig. 2). The SLE patient developed ON within 2 years of corticosteroids therapy and a cumulative corticosteroids dose of approximately 12.8 g. During the period of treatment, time of glucocorticoids therapy exceeding 20 mg was for more than 200 days (Fig. 3). After multidisciplinary consultations, the patient finally received high-dose methylprednisolone (0.4 g daily for 2 days) for the third time and multiple intravenous cyclophosphamide (350 mg daily for 2 days) pulse therapies. Meanwhile, the patient was started on oral calcitriol (0.25 μg daily) therapy. In addition, antiplatelet medication dipyridamole (75 mg daily) was taken as adjuvant therapy to prevent thrombus formation. The patient's symptoms alleviated more quickly than expected. Three weeks later, the swelling in her left knee subsided. Her self-reporting pain score decreased from 9 to 4 and walking time increased from 45 minutes to 90 minutes per day. Nearly 5 weeks later, the pain in double knee joint disappeared and the girl could walk without difficulty. At the present stage, surgical interventions are unnecessary for the patient. Alendronate has been recruited into our next therapeutic plan. Now the patient is still undergoing long-term follow-up and treatment.
Figure 1 Bilateral knee joint magnetic resonance imaging appearance of the systemic lupus erythematosus patient with osteonecrosis (A) and (B) Sagittal magnetic resonance imagings of left knee joint. (C) and (D) Sagittal magnetic resonance imaging of right knee joint. The figure demonstrated irregular bone destruction and bone hyperplasia lesions on bilateral distal femur and proximal tibia, presenting geographic alterations.
Figure 2 Renal pathological histology of the systemic lupus erythematosus patient with osteonecrosis. Frozen-section showed IgG+++ IgA+++ IgM++ C3+++ C4++ C1q++ Fib+ granular deposition in the capillary loops and mesangium. The renal pathologic diagnosis was in accordance with class IV diffuse proliferative lupus nephritis [IV-G(A/C)].
Figure 3 Methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient with osteonecrosis. The figure displays methylprednisolone dosage during the treatment of the systemic lupus erythematosus patient in our case. High-dose methylprednisolone pulse therapies were given 3 times, respectively at the 9th day, 60th day, and 633th day since treatment started. Treatment time of corticosteroids exceeding 20 mg was for more than 200 d.
3 Discussion
Osteonecrosis is a known complication of SLE, which mainly affects female SLE patients of childbearing age. Our case presented a 13.3-year-old female SLE patient who developed juvenile multifocal ON with bilateral knee joint involvement. Compared with adolescent and adult SLE patients, pediatric patients have remarkably lower rates of ON. Multifocal ON, with an estimated morbidity of 3% in SLE patients, is rare in juvenile-onset subjects. To our knowledge, previous studies concerning juvenile-onset SLE patients with ON are very limited. The first reported pediatric SLE patients developing ON can be dated back to 1974, in an article published by Hurley et al.[11] Among the 4 patients with avascular necrosis, the youngest was 14 years old when ON was diagnosed in her left hip. In 2010, Nakamura et al[2] investigated 18 pediatric SLE patients (<15 years old) and 25 adolescent SLE patients (15–20 years old), and reported the youngest patients with ON in the hip and knee was 14.9 and 15.5 years old, respectively. They held the view that ON did not develop in patients younger than 14 years old. In 2015, Gurion et al[3] followed up 201 pediatric SLE patients for 36 months and 17 subjects developed or had a history of avascular necrosis. The average age of ON subjects was 16.5 years old and 8 subjects had developed multifocal involvement. Owing to the lack of detailed individual data, the youngest multifocal ON subject was unknown in the study. Based on the existing data, the patient in our case may be the youngest SLE patient who developed multifocal ON. Compared with previous reported juvenile SLE patients, our case suggested a younger age tendency of ON onset and multifocal involvements at the first attack among the other reported pediatric cases.
Corticosteroids are widely applied as the first-line treatment of SLE, and their long-term exposure is closely associated with progress of ON.[12–15] According to a meta analysis, each 10 mg per day increase of corticosteroids was associated with a 3.6% increase in ON occurrence. SLE patients treated with corticosteroids greater than 20 mg per day demonstrated significantly higher odds of ON than those treated with less than 20 mg per day.[15] But corticosteroids are not the only etiology for developing ON. The underlying mechanisms of ON in SLE are linked with internal and external complicated risk factors. Firstly, multiple factors associated with SLE disease itself can contribute to the development of ON. Arthritis, cushingoid, gastrointestinal involvement, hypertension, pleuritis, renal disease, and vasculitis were observed with ON in SLE patients.[12] Additionally, hypercoagulable state and antiphospholipid antibodies which are closely associated with thrombogenesis, can participate in the pathogenesis of ON in SLE.[16,17] Furthermore, researchers found SLE disease activity was a sensitive predictor of ON. Patients with SLEDAI ≥ 8 were significantly at a higher risk of suffering from ON.[18] Secondly, cytotoxic drugs are also a risk factor of ON.[12,19] Long-term high cumulative corticosteroids dose and immunosuppressant have a synergistic effect on the development of avascular necrosis in SLE patients.[19] Thirdly, recent studies revealed gene polymorphisms may increase the risk of ON in SLE patients. Nitric oxide synthase 3 (NOS3) and complement receptor type 2 (CR2) gene polymorphisms, single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene were significantly associated with risk of femoral head osteonecrosis in SLE.[20–22] Fourthly, deficiency of important immunoregulatory mediator Vitamin D, has been found to be associated with avascular ON in a pediatric lupus erythematosus trial.[3] Therefore, interaction of multiple risk factors in our case jointly promoted the formation of ON.
There existed limitations during the treatment of our SLE patient. The patient in our case started oral calcitriol therapy after her knee joint ON was diagnosed. After taking medicine, her Vitamin D deficiency improved and her symptomatic ON was relieved. Meanwhile, antiplatelet aggregation drug dipyridamole also played an important role in the inhibition of thrombi formation and ON progress. Alendronate has been recruited into our next therapeutic plan as well. It has been confirmed that alendronate can effectively alleviate pain and delay the progress of ON, avoiding surgical interventions.[23] A recent Japanese study discovered early use of alendronate have a preventive effect against bone loss in corticosteroids-treated juvenile-onset rheumatic diseases.[24] These measures are beneficial for slowing ON deterioration and avoiding surgeries. However, long-term corticosteriods and immunosuppressors, multiple pulse therapies are still used to control active lupus and nephritis. As discussed before, corticosteroids and immunosuppressors together promote the development of ON, which is contradictory to the intention of preventing ON progress. The method of balancing corticosteriods and immunosuppressors in the treatment of SLE and prevention of ON is a challenging problem and deserves further exploration.
Several novel methods for ON prevention and treatment have been widely studied. Anti-coagulant ingredient warfarin and hypolipidemic drug statins can significantly decrease the risk of ON induced by steroids.[25–27] In addition, physical therapies such as extracorporeal shockwave therapy (ESWT), hyperbaric oxygen therapy, and pulsed electromagnetic therapy have been proved to stimulate neovascularization, increase intracellular oxygen, and reduce inflammation reactions in ON lesions.[28–31] Implantation of autologous bone marrow mesenchymal stem cells is a promising treatment of osteonecrosis of femoral head, significantly reducing the risk of femoral head collapse and the need of total hip replacement.[32–34]
In summary, the present case report described a 13.3-year-old female SLE patient who developed multifocal ON in her bilateral knee joint. We believe that this case report and the literature review on the underlying mechanisms of ON in SLE patients and the relevant therapeutic methods and preventive measures would help the physicians and pediatricians to have more comprehensive and profound understanding of pathogenesis and treatments of ON in SLE.
Acknowledgments
We are grateful for the assistance from Department of Rheumatology Immunology and Allergy, Children's Hospital, Zhejiang University School of Medicine in data collection, and the participation of the systemic lupus erythematosus patient in our study.
Author contributions
Investigation: Wenyuan Jin, Xinghui Yang, Meiping Lu.
Visualization: Xinghui Yang.
Writing – original draft: Wenyuan Jin.
Writing – review & editing: Meiping Lu, Wenyuan Jin.
Abbreviations: ABCB1 = adenosine triphosphate-binding cassette B1, ANA = antinuclear antibodies, CR2 = complement receptor type 2, ESR = erythrocyte sedimentation rate, ESWT = extracorporeal shockwave therapy, MRI = magnetic resonance imaging, NOS3 = nitric oxide synthase 3, ON = osteonecrosis, SLE = systemic lupus erythematosus, SLEDAI = system lupus erythematosus disease activity index, SNPs = single nucleotide polymorphisms, VEGF = vascular endothelial growth factor.
How to cite this article: Jin W, Yang X, Lu M. Juvenile-onset multifocal osteonecrosis in systemic lupus erythematosus: A case report. Medicine. 2021;100:2(e24031).
The authors have no funding and conflicts of interest to disclose.
The study has obtained approval from the Clinical Research Ethics Committee of Children's Hospital, Zhejiang University School of Medicine.
Written informed consent was obtained from the patient's parents for publication of this case report.
All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | Recovered | ReactionOutcome | CC BY | 33466148 | 18,833,123 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: Case report.
BACKGROUND
Thrombocytopenia (TP) is a common complication of childhood-onset systemic lupus erythematosus (SLE), and can range from mild to life-threatening. However, severe TP with multiple hemorrhagic complications is very rare and often predicts a poor prognosis. We describe a 12-year-old Chinese girl who had a history of idiopathic thrombocytopenic purpura who developed SLE that presented as subdural hemorrhage and retinal hemorrhage because of severe TP.
A 12-year-old girl was admitted into our hospital because of fever, purpura, and gum bleeding lasting for 12 days. She had a history of idiopathic thrombocytopenic purpura 2 years ago previously.
METHODS
SLE was diagnosed according to American College of Rheumatology classification criteria. Subdural hemorrhage and retinal hemorrhage were diagnosed based on brain MRI and funduscopy. Severe TP was defined as platelet count <20 × 109/L.
METHODS
She was treated first with intravenous immunoglobulin, but it was not efficacious. High-dose methylprednisolone showed short-term efficacy. Then, she was given a glucocorticoid and cyclosporine A plus mycophenolate mofetil.
RESULTS
Fever, purpura, and gum bleeding were resolved before hospital discharge. Subdural hemorrhage and left hemorrhagic retinopathy were improved remarkably. She had a durable response to refractory TP with no adverse effects during >1-year follow-up.
CONCLUSIONS
Isolated TP may be an early symptom of childhood-onset SLE . A child with severe TP is prone to develop life-threatening hemorrhagic complications. Glucocorticoids and combined immunosuppressive drugs had a durable response to refractory TP in this patient with no adverse effects.
1 Introduction
Systemic lupus erythematosus (SLE) is a multisystem illness. Patients with childhood-onset systemic lupus erythematosus (c-SLE) have a more severe course and organ damage than patients with adult-onset SLE.[1,2] Up to 40% of patients with SLE develop thrombocytopenia (TP). TP is a reliable marker suggesting active disease and often predicts a poor prognosis.[3] Severe TP is relatively uncommon, but it can result in visceral hemorrhage and death.
Although spared from kidney involvement, our pediatric patient developed intracranial and retinal hemorrhages, which were vision-threatening. To date, such a pediatric case has not been reported before.
2 Case report
A 12-year-old girl with a history of idiopathic thrombocytopenic purpura of 2-year duration received intravenous immunoglobulin (IVIG; 1 g/kg bodyweight) treatment for prolonged fever, purpura, gum bleeding, and TP at a local hospital, but showed no response. She developed myalgia, arthralgia, headache, and severe TP (platelet count, 2 × 109/L) lasting for 12 days and was transferred to our hospital.
Upon physical examination, dental ulcers, gum bleeding, purpura on lower extremities, mild hepatomegaly, arthritis on elbow joints, and painless loss of vision in her left eye were noted. Neurological findings appeared normal.
Complete blood cell counts showed a normal white blood cell count (8.28 × 109/L), normocytic normochromic anemia (hemoglobin, 84 g/L) and severe TP (platelet count, 6 × 109/L). Biochemical investigations showed levels of alanine aminotransferase to be 43 U/L, aspartate aminotransferase to be 133 U/L, lactate dehydrogenase to be 800 U/L, and with normal blood urea nitrogen and serum creatinine. Other laboratory findings revealed increased erythrocyte sedimentation rate (117 mm/h), hypocomplementemia (complement C3, 0.4 g/L; complement C4, 0.08 g/L), positivity for serum anti-nuclear antibodies (1:3200), anti-Sm, anti-SS-A, anti-Sm/nRNP, anti-chromatin, anti-RNP 68, anti-RNP A antibodies, and negative for serum anti-dsDNA antibody. The Coombs’ test was 2+, and the patient was negative for antiphospholipid antibody, lupus anticoagulant, and antiplatelet antibody. The activated partial thromboplastin time was 36.6 second, and prothrombin time was 14.2 second.
Urinalyses were normal. Ultrasound of the abdomen revealed hepatosplenomegaly. Subsequent magnetic resonance imaging of the head showed a subacute subdural hemorrhage in bilateral cerebral hemispheres and cerebellum, and multiple demyelinating lesions in the bilateral frontotemporal cortex and bilateral cerebellar hemispheres (Fig. 1A). Funduscopic examination indicated severe retinal hemorrhage in the left eye (Fig. 2A). Based on these data, a diagnosis of severe SLE was established.
Figure 1 Magnetic resonance imaging (MRI) of the brain at different times. (A) Upon presentation, MRI showed a subacute subdural hemorrhage (white arrow) and multiple demyelinating lesions (red arrow) in bilateral cerebral hemispheres and cerebellum. (B) One month later and (C) 4 months later, MRI showed that the subdural hemorrhage had been absorbed completely, and multiple demyelinating lesions became smaller or disappeared in the cerebellum.
Figure 2 Fundus images. (A) Massive retinal hemorrhage on her left eye upon presentation. (B) The retinal hemorrhage on her left eye was absorbed partially after 2 weeks. (C) The retinal hemorrhage on her left eye was absorbed completely after 3 months.
Emergency treatment was initiated with platelet transfusion, IVIG (1 g/kg) and 2 pulses of methylprednisolone (mPSL) with 80 mg/pulse intravenous infusion. Nonetheless, the platelet number failed to increase. On day-3 of hospitalization, she was given high-dose (500 mg) mPSL daily for 3 days followed by high-dose (60 mg/d) prednisolone. The platelet count continued to decrease, so she was also given cyclosporine-A (CSA) (75 mg, q12 hour, p.o.). After intravenous high-dose mPSL, the fever resolved, and the anemia and TP improved. On day-7 of hospitalization, the hemoglobin level increased to 104 g/L, platelet count returned to 197 × 109/L but decreased to 48 × 109/L on day-15. Due to high SLE activity (Systemic Lupus Erythematosus Disease Activity Index was 30) and the very few megakaryocytes in bone marrow (1 megakaryocyte count per slide), she was treated with high-dose (750 mg/d for 4 days) mPSL plus mycophenolate mofetil (MMF). The platelet count continued to fluctuate significantly. Fortunately, her symptoms were much improved. By day-26 of hospitalization, the platelet count began to increase steadily and reached 187 × 109/L on day-42. Then, she was discharged and continued with, CSA, and MMF. Her clinical course in hospital is illustrated in Figure 3.
Figure 3 The clinical course of our patient in hospital.
The subdural hemorrhage (Fig. 1B, C) and left hemorrhagic retinopathy (Fig. 2B and 2C) improved remarkably. Her platelet count decreased to 47 × 109/L because of a respiratory infection 6 months after discharge from hospital, but recovered to 148 × 109/L after 1-week antibiotic treatment. The patient was followed up for >1 year after hospital discharge. The dose of oral drugs was tapered gradually. Relevant side effects did not appear.
3 Discussion
TP is a common manifestation in SLE, and often predicts a poor prognosis. The pathogenesis of TP in SLE is not known. The presumed mechanisms include: platelet destruction and deletion by autoantibodies in the peripheral circulation; inhibition of the development and maturation of megakaryocytes in bone marrow; consumption of platelets because of thrombotic microangiopathy/thrombotic thrombocytopenic purpura (TTP); secondary antiphospholipid syndrome (APS). These mechanisms often coexist.[3] Inhibition of the development and maturation of megakaryocytes in bone marrow is an important factor. Zhao et al[3] reported that patients with a megakaryocyte count in bone marrow <20/slide have a poor clinical response to immunotherapy. In our case, the megakaryocyte number decreased significantly, with 1 megakaryocyte count per slide justifying that TP was refractory to immunotherapy.
Retinal hemorrhage and subdural hemorrhage occurring together are unusual in SLE (especially in c-SLE). About one-third of SLE patients develop ocular manifestations, with 7% to 29% showing retinal involvement. Retinopathy is probably caused by “cotton wool” spots, retinal haemorrhage and microvascular infarcts.[4,5] SLE patients are prone to develop hemorrhagic complications. Spontaneous intracranial hemorrhage is the most serious complication of TP, and is potentially life-threatening. The mechanisms of intracranial hemorrhage are incompletely understood, but several related causes have been summarized,[6] including hypercholesterolemia, hypertension, prolonged treatment with corticosteroids, angiopathy, and aneurysms caused by SLE. Moreover, TP is also an important risk factor. In a single-center retrospective study, 26 out of 6653 SLE cases had intracranial hemorrhage. In these 26 cases, 53.8% had TP, and TP was an independent risk factor for intracranial hemorrhage induced by SLE.[7] That finding is consistent with that of our patient, and the hemorrhages were absorbed while the platelet count returned to normal.
TP treatment in SLE is dependent upon the presentation of systemic disease. Treatment of TP in SLE needs to be specific. Glucocorticoids are regarded as first-line therapy in severe TP but very few patients have sustained remission. IVIG shows rapid, but not long-term, efficacy in patients suffering active bleeding. Hence, immunosuppressive therapy may be warranted.[8] One case of bilateral hemorrhagic retinopathy treated with azathioprine showed the disappearance of Roth spots within 6 weeks of treatment.[9] CSA treatment in patients presenting with TP associated with SLE has shown optimal relief.[10] Broad-spectrum immunosuppressants such as cyclophosphamide have been found to be efficacious in patients with refractory TP in SLE.[11] Some case studies have shown that MMF and tacrolimus can be used to treat TP successfully.[11,12,13] However, some TP patients are refractory to conventional therapies. Biologics could be a good choice for patients with TP in SLE. In a study by Olfat and colleagues,[14] 24 refractory patients with c-SLE were treated with rituximab, of whom 16 had TP, 5 had hemolytic anemia, and 3 had both. Only 1 patient failed to respond to rituximab. All patients tolerated rituximab treatment. However, caution should be exercised when considering rituximab for patients with preexisting hypogammaglobulinemia. According to Lei and colleagues, c-SLE patients intolerant of rituximab who used another B cell-depleting agent, ofatumumab, also obtained a therapeutic effect.[15] Additional treatments, such as plasmapheresis and thrombopoietin receptor agonists, can be efficacious in patients with refractory TP and active bleeding. For some patients with refractory TP non-responsive to medical therapies, splenectomy may be an important alternative.[16] Successful treatment for a-SLE is well documented, but not for c-SLE. Our case had severe TP with potential organ bleeding, so we initiated emergency treatment at an early stage: platelet transfusion, IVIG, mPSL, and CSA. The platelet count fluctuated significantly, so we added MMF which, ultimately, improved TP.
4 Conclusions
Spontaneous subdural hemorrhage with retinal hemorrhage as a consequence of TP in c-SLE is rare. However, we successfully treated our patient with a glucocorticoid combined with 2 immunosuppressants. We consider this regimen to be safe and efficacious treatment in severe TP of c-SLE.
Author contributions
Conceptualization: Ping Lu, Huiling Lu.
Data curation: Ping Lu, Huiling Lu.
Project administration: Yu Wen, Ping Lu, Huiling Lu.
Supervision: Xiufen Hu.
Writing – original draft: Yu Wen.
Writing – review & editing: Yu Wen, Xiufen Hu.
Abbreviations: CSA = cyclosporin-A, c-SLE = childhood-onset systemic lupus erythematous, IVIG = intravenous immunoglobulin, MMF = mycophenolate mofetil, mPSL = methylprednisolone, SLE = systemic lupus erythematosus, TP = thrombocytopenia.
How to cite this article: Wen Y, Lu P, Lu H, Hu X. Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: case report. Medicine. 2021;100:2(e24231).
Written informed consent was obtained from the patient's mother for publication of this case report and accompanying images.
The study protocol was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33466204 | 18,939,623 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: Case report.
BACKGROUND
Thrombocytopenia (TP) is a common complication of childhood-onset systemic lupus erythematosus (SLE), and can range from mild to life-threatening. However, severe TP with multiple hemorrhagic complications is very rare and often predicts a poor prognosis. We describe a 12-year-old Chinese girl who had a history of idiopathic thrombocytopenic purpura who developed SLE that presented as subdural hemorrhage and retinal hemorrhage because of severe TP.
A 12-year-old girl was admitted into our hospital because of fever, purpura, and gum bleeding lasting for 12 days. She had a history of idiopathic thrombocytopenic purpura 2 years ago previously.
METHODS
SLE was diagnosed according to American College of Rheumatology classification criteria. Subdural hemorrhage and retinal hemorrhage were diagnosed based on brain MRI and funduscopy. Severe TP was defined as platelet count <20 × 109/L.
METHODS
She was treated first with intravenous immunoglobulin, but it was not efficacious. High-dose methylprednisolone showed short-term efficacy. Then, she was given a glucocorticoid and cyclosporine A plus mycophenolate mofetil.
RESULTS
Fever, purpura, and gum bleeding were resolved before hospital discharge. Subdural hemorrhage and left hemorrhagic retinopathy were improved remarkably. She had a durable response to refractory TP with no adverse effects during >1-year follow-up.
CONCLUSIONS
Isolated TP may be an early symptom of childhood-onset SLE . A child with severe TP is prone to develop life-threatening hemorrhagic complications. Glucocorticoids and combined immunosuppressive drugs had a durable response to refractory TP in this patient with no adverse effects.
1 Introduction
Systemic lupus erythematosus (SLE) is a multisystem illness. Patients with childhood-onset systemic lupus erythematosus (c-SLE) have a more severe course and organ damage than patients with adult-onset SLE.[1,2] Up to 40% of patients with SLE develop thrombocytopenia (TP). TP is a reliable marker suggesting active disease and often predicts a poor prognosis.[3] Severe TP is relatively uncommon, but it can result in visceral hemorrhage and death.
Although spared from kidney involvement, our pediatric patient developed intracranial and retinal hemorrhages, which were vision-threatening. To date, such a pediatric case has not been reported before.
2 Case report
A 12-year-old girl with a history of idiopathic thrombocytopenic purpura of 2-year duration received intravenous immunoglobulin (IVIG; 1 g/kg bodyweight) treatment for prolonged fever, purpura, gum bleeding, and TP at a local hospital, but showed no response. She developed myalgia, arthralgia, headache, and severe TP (platelet count, 2 × 109/L) lasting for 12 days and was transferred to our hospital.
Upon physical examination, dental ulcers, gum bleeding, purpura on lower extremities, mild hepatomegaly, arthritis on elbow joints, and painless loss of vision in her left eye were noted. Neurological findings appeared normal.
Complete blood cell counts showed a normal white blood cell count (8.28 × 109/L), normocytic normochromic anemia (hemoglobin, 84 g/L) and severe TP (platelet count, 6 × 109/L). Biochemical investigations showed levels of alanine aminotransferase to be 43 U/L, aspartate aminotransferase to be 133 U/L, lactate dehydrogenase to be 800 U/L, and with normal blood urea nitrogen and serum creatinine. Other laboratory findings revealed increased erythrocyte sedimentation rate (117 mm/h), hypocomplementemia (complement C3, 0.4 g/L; complement C4, 0.08 g/L), positivity for serum anti-nuclear antibodies (1:3200), anti-Sm, anti-SS-A, anti-Sm/nRNP, anti-chromatin, anti-RNP 68, anti-RNP A antibodies, and negative for serum anti-dsDNA antibody. The Coombs’ test was 2+, and the patient was negative for antiphospholipid antibody, lupus anticoagulant, and antiplatelet antibody. The activated partial thromboplastin time was 36.6 second, and prothrombin time was 14.2 second.
Urinalyses were normal. Ultrasound of the abdomen revealed hepatosplenomegaly. Subsequent magnetic resonance imaging of the head showed a subacute subdural hemorrhage in bilateral cerebral hemispheres and cerebellum, and multiple demyelinating lesions in the bilateral frontotemporal cortex and bilateral cerebellar hemispheres (Fig. 1A). Funduscopic examination indicated severe retinal hemorrhage in the left eye (Fig. 2A). Based on these data, a diagnosis of severe SLE was established.
Figure 1 Magnetic resonance imaging (MRI) of the brain at different times. (A) Upon presentation, MRI showed a subacute subdural hemorrhage (white arrow) and multiple demyelinating lesions (red arrow) in bilateral cerebral hemispheres and cerebellum. (B) One month later and (C) 4 months later, MRI showed that the subdural hemorrhage had been absorbed completely, and multiple demyelinating lesions became smaller or disappeared in the cerebellum.
Figure 2 Fundus images. (A) Massive retinal hemorrhage on her left eye upon presentation. (B) The retinal hemorrhage on her left eye was absorbed partially after 2 weeks. (C) The retinal hemorrhage on her left eye was absorbed completely after 3 months.
Emergency treatment was initiated with platelet transfusion, IVIG (1 g/kg) and 2 pulses of methylprednisolone (mPSL) with 80 mg/pulse intravenous infusion. Nonetheless, the platelet number failed to increase. On day-3 of hospitalization, she was given high-dose (500 mg) mPSL daily for 3 days followed by high-dose (60 mg/d) prednisolone. The platelet count continued to decrease, so she was also given cyclosporine-A (CSA) (75 mg, q12 hour, p.o.). After intravenous high-dose mPSL, the fever resolved, and the anemia and TP improved. On day-7 of hospitalization, the hemoglobin level increased to 104 g/L, platelet count returned to 197 × 109/L but decreased to 48 × 109/L on day-15. Due to high SLE activity (Systemic Lupus Erythematosus Disease Activity Index was 30) and the very few megakaryocytes in bone marrow (1 megakaryocyte count per slide), she was treated with high-dose (750 mg/d for 4 days) mPSL plus mycophenolate mofetil (MMF). The platelet count continued to fluctuate significantly. Fortunately, her symptoms were much improved. By day-26 of hospitalization, the platelet count began to increase steadily and reached 187 × 109/L on day-42. Then, she was discharged and continued with, CSA, and MMF. Her clinical course in hospital is illustrated in Figure 3.
Figure 3 The clinical course of our patient in hospital.
The subdural hemorrhage (Fig. 1B, C) and left hemorrhagic retinopathy (Fig. 2B and 2C) improved remarkably. Her platelet count decreased to 47 × 109/L because of a respiratory infection 6 months after discharge from hospital, but recovered to 148 × 109/L after 1-week antibiotic treatment. The patient was followed up for >1 year after hospital discharge. The dose of oral drugs was tapered gradually. Relevant side effects did not appear.
3 Discussion
TP is a common manifestation in SLE, and often predicts a poor prognosis. The pathogenesis of TP in SLE is not known. The presumed mechanisms include: platelet destruction and deletion by autoantibodies in the peripheral circulation; inhibition of the development and maturation of megakaryocytes in bone marrow; consumption of platelets because of thrombotic microangiopathy/thrombotic thrombocytopenic purpura (TTP); secondary antiphospholipid syndrome (APS). These mechanisms often coexist.[3] Inhibition of the development and maturation of megakaryocytes in bone marrow is an important factor. Zhao et al[3] reported that patients with a megakaryocyte count in bone marrow <20/slide have a poor clinical response to immunotherapy. In our case, the megakaryocyte number decreased significantly, with 1 megakaryocyte count per slide justifying that TP was refractory to immunotherapy.
Retinal hemorrhage and subdural hemorrhage occurring together are unusual in SLE (especially in c-SLE). About one-third of SLE patients develop ocular manifestations, with 7% to 29% showing retinal involvement. Retinopathy is probably caused by “cotton wool” spots, retinal haemorrhage and microvascular infarcts.[4,5] SLE patients are prone to develop hemorrhagic complications. Spontaneous intracranial hemorrhage is the most serious complication of TP, and is potentially life-threatening. The mechanisms of intracranial hemorrhage are incompletely understood, but several related causes have been summarized,[6] including hypercholesterolemia, hypertension, prolonged treatment with corticosteroids, angiopathy, and aneurysms caused by SLE. Moreover, TP is also an important risk factor. In a single-center retrospective study, 26 out of 6653 SLE cases had intracranial hemorrhage. In these 26 cases, 53.8% had TP, and TP was an independent risk factor for intracranial hemorrhage induced by SLE.[7] That finding is consistent with that of our patient, and the hemorrhages were absorbed while the platelet count returned to normal.
TP treatment in SLE is dependent upon the presentation of systemic disease. Treatment of TP in SLE needs to be specific. Glucocorticoids are regarded as first-line therapy in severe TP but very few patients have sustained remission. IVIG shows rapid, but not long-term, efficacy in patients suffering active bleeding. Hence, immunosuppressive therapy may be warranted.[8] One case of bilateral hemorrhagic retinopathy treated with azathioprine showed the disappearance of Roth spots within 6 weeks of treatment.[9] CSA treatment in patients presenting with TP associated with SLE has shown optimal relief.[10] Broad-spectrum immunosuppressants such as cyclophosphamide have been found to be efficacious in patients with refractory TP in SLE.[11] Some case studies have shown that MMF and tacrolimus can be used to treat TP successfully.[11,12,13] However, some TP patients are refractory to conventional therapies. Biologics could be a good choice for patients with TP in SLE. In a study by Olfat and colleagues,[14] 24 refractory patients with c-SLE were treated with rituximab, of whom 16 had TP, 5 had hemolytic anemia, and 3 had both. Only 1 patient failed to respond to rituximab. All patients tolerated rituximab treatment. However, caution should be exercised when considering rituximab for patients with preexisting hypogammaglobulinemia. According to Lei and colleagues, c-SLE patients intolerant of rituximab who used another B cell-depleting agent, ofatumumab, also obtained a therapeutic effect.[15] Additional treatments, such as plasmapheresis and thrombopoietin receptor agonists, can be efficacious in patients with refractory TP and active bleeding. For some patients with refractory TP non-responsive to medical therapies, splenectomy may be an important alternative.[16] Successful treatment for a-SLE is well documented, but not for c-SLE. Our case had severe TP with potential organ bleeding, so we initiated emergency treatment at an early stage: platelet transfusion, IVIG, mPSL, and CSA. The platelet count fluctuated significantly, so we added MMF which, ultimately, improved TP.
4 Conclusions
Spontaneous subdural hemorrhage with retinal hemorrhage as a consequence of TP in c-SLE is rare. However, we successfully treated our patient with a glucocorticoid combined with 2 immunosuppressants. We consider this regimen to be safe and efficacious treatment in severe TP of c-SLE.
Author contributions
Conceptualization: Ping Lu, Huiling Lu.
Data curation: Ping Lu, Huiling Lu.
Project administration: Yu Wen, Ping Lu, Huiling Lu.
Supervision: Xiufen Hu.
Writing – original draft: Yu Wen.
Writing – review & editing: Yu Wen, Xiufen Hu.
Abbreviations: CSA = cyclosporin-A, c-SLE = childhood-onset systemic lupus erythematous, IVIG = intravenous immunoglobulin, MMF = mycophenolate mofetil, mPSL = methylprednisolone, SLE = systemic lupus erythematosus, TP = thrombocytopenia.
How to cite this article: Wen Y, Lu P, Lu H, Hu X. Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: case report. Medicine. 2021;100:2(e24231).
Written informed consent was obtained from the patient's mother for publication of this case report and accompanying images.
The study protocol was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | HUMAN IMMUNOGLOBULIN G, METHYLPREDNISOLONE, PREDNISOLONE | DrugsGivenReaction | CC BY | 33466204 | 18,939,623 | 2021-01-15 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: Case report.
BACKGROUND
Thrombocytopenia (TP) is a common complication of childhood-onset systemic lupus erythematosus (SLE), and can range from mild to life-threatening. However, severe TP with multiple hemorrhagic complications is very rare and often predicts a poor prognosis. We describe a 12-year-old Chinese girl who had a history of idiopathic thrombocytopenic purpura who developed SLE that presented as subdural hemorrhage and retinal hemorrhage because of severe TP.
A 12-year-old girl was admitted into our hospital because of fever, purpura, and gum bleeding lasting for 12 days. She had a history of idiopathic thrombocytopenic purpura 2 years ago previously.
METHODS
SLE was diagnosed according to American College of Rheumatology classification criteria. Subdural hemorrhage and retinal hemorrhage were diagnosed based on brain MRI and funduscopy. Severe TP was defined as platelet count <20 × 109/L.
METHODS
She was treated first with intravenous immunoglobulin, but it was not efficacious. High-dose methylprednisolone showed short-term efficacy. Then, she was given a glucocorticoid and cyclosporine A plus mycophenolate mofetil.
RESULTS
Fever, purpura, and gum bleeding were resolved before hospital discharge. Subdural hemorrhage and left hemorrhagic retinopathy were improved remarkably. She had a durable response to refractory TP with no adverse effects during >1-year follow-up.
CONCLUSIONS
Isolated TP may be an early symptom of childhood-onset SLE . A child with severe TP is prone to develop life-threatening hemorrhagic complications. Glucocorticoids and combined immunosuppressive drugs had a durable response to refractory TP in this patient with no adverse effects.
1 Introduction
Systemic lupus erythematosus (SLE) is a multisystem illness. Patients with childhood-onset systemic lupus erythematosus (c-SLE) have a more severe course and organ damage than patients with adult-onset SLE.[1,2] Up to 40% of patients with SLE develop thrombocytopenia (TP). TP is a reliable marker suggesting active disease and often predicts a poor prognosis.[3] Severe TP is relatively uncommon, but it can result in visceral hemorrhage and death.
Although spared from kidney involvement, our pediatric patient developed intracranial and retinal hemorrhages, which were vision-threatening. To date, such a pediatric case has not been reported before.
2 Case report
A 12-year-old girl with a history of idiopathic thrombocytopenic purpura of 2-year duration received intravenous immunoglobulin (IVIG; 1 g/kg bodyweight) treatment for prolonged fever, purpura, gum bleeding, and TP at a local hospital, but showed no response. She developed myalgia, arthralgia, headache, and severe TP (platelet count, 2 × 109/L) lasting for 12 days and was transferred to our hospital.
Upon physical examination, dental ulcers, gum bleeding, purpura on lower extremities, mild hepatomegaly, arthritis on elbow joints, and painless loss of vision in her left eye were noted. Neurological findings appeared normal.
Complete blood cell counts showed a normal white blood cell count (8.28 × 109/L), normocytic normochromic anemia (hemoglobin, 84 g/L) and severe TP (platelet count, 6 × 109/L). Biochemical investigations showed levels of alanine aminotransferase to be 43 U/L, aspartate aminotransferase to be 133 U/L, lactate dehydrogenase to be 800 U/L, and with normal blood urea nitrogen and serum creatinine. Other laboratory findings revealed increased erythrocyte sedimentation rate (117 mm/h), hypocomplementemia (complement C3, 0.4 g/L; complement C4, 0.08 g/L), positivity for serum anti-nuclear antibodies (1:3200), anti-Sm, anti-SS-A, anti-Sm/nRNP, anti-chromatin, anti-RNP 68, anti-RNP A antibodies, and negative for serum anti-dsDNA antibody. The Coombs’ test was 2+, and the patient was negative for antiphospholipid antibody, lupus anticoagulant, and antiplatelet antibody. The activated partial thromboplastin time was 36.6 second, and prothrombin time was 14.2 second.
Urinalyses were normal. Ultrasound of the abdomen revealed hepatosplenomegaly. Subsequent magnetic resonance imaging of the head showed a subacute subdural hemorrhage in bilateral cerebral hemispheres and cerebellum, and multiple demyelinating lesions in the bilateral frontotemporal cortex and bilateral cerebellar hemispheres (Fig. 1A). Funduscopic examination indicated severe retinal hemorrhage in the left eye (Fig. 2A). Based on these data, a diagnosis of severe SLE was established.
Figure 1 Magnetic resonance imaging (MRI) of the brain at different times. (A) Upon presentation, MRI showed a subacute subdural hemorrhage (white arrow) and multiple demyelinating lesions (red arrow) in bilateral cerebral hemispheres and cerebellum. (B) One month later and (C) 4 months later, MRI showed that the subdural hemorrhage had been absorbed completely, and multiple demyelinating lesions became smaller or disappeared in the cerebellum.
Figure 2 Fundus images. (A) Massive retinal hemorrhage on her left eye upon presentation. (B) The retinal hemorrhage on her left eye was absorbed partially after 2 weeks. (C) The retinal hemorrhage on her left eye was absorbed completely after 3 months.
Emergency treatment was initiated with platelet transfusion, IVIG (1 g/kg) and 2 pulses of methylprednisolone (mPSL) with 80 mg/pulse intravenous infusion. Nonetheless, the platelet number failed to increase. On day-3 of hospitalization, she was given high-dose (500 mg) mPSL daily for 3 days followed by high-dose (60 mg/d) prednisolone. The platelet count continued to decrease, so she was also given cyclosporine-A (CSA) (75 mg, q12 hour, p.o.). After intravenous high-dose mPSL, the fever resolved, and the anemia and TP improved. On day-7 of hospitalization, the hemoglobin level increased to 104 g/L, platelet count returned to 197 × 109/L but decreased to 48 × 109/L on day-15. Due to high SLE activity (Systemic Lupus Erythematosus Disease Activity Index was 30) and the very few megakaryocytes in bone marrow (1 megakaryocyte count per slide), she was treated with high-dose (750 mg/d for 4 days) mPSL plus mycophenolate mofetil (MMF). The platelet count continued to fluctuate significantly. Fortunately, her symptoms were much improved. By day-26 of hospitalization, the platelet count began to increase steadily and reached 187 × 109/L on day-42. Then, she was discharged and continued with, CSA, and MMF. Her clinical course in hospital is illustrated in Figure 3.
Figure 3 The clinical course of our patient in hospital.
The subdural hemorrhage (Fig. 1B, C) and left hemorrhagic retinopathy (Fig. 2B and 2C) improved remarkably. Her platelet count decreased to 47 × 109/L because of a respiratory infection 6 months after discharge from hospital, but recovered to 148 × 109/L after 1-week antibiotic treatment. The patient was followed up for >1 year after hospital discharge. The dose of oral drugs was tapered gradually. Relevant side effects did not appear.
3 Discussion
TP is a common manifestation in SLE, and often predicts a poor prognosis. The pathogenesis of TP in SLE is not known. The presumed mechanisms include: platelet destruction and deletion by autoantibodies in the peripheral circulation; inhibition of the development and maturation of megakaryocytes in bone marrow; consumption of platelets because of thrombotic microangiopathy/thrombotic thrombocytopenic purpura (TTP); secondary antiphospholipid syndrome (APS). These mechanisms often coexist.[3] Inhibition of the development and maturation of megakaryocytes in bone marrow is an important factor. Zhao et al[3] reported that patients with a megakaryocyte count in bone marrow <20/slide have a poor clinical response to immunotherapy. In our case, the megakaryocyte number decreased significantly, with 1 megakaryocyte count per slide justifying that TP was refractory to immunotherapy.
Retinal hemorrhage and subdural hemorrhage occurring together are unusual in SLE (especially in c-SLE). About one-third of SLE patients develop ocular manifestations, with 7% to 29% showing retinal involvement. Retinopathy is probably caused by “cotton wool” spots, retinal haemorrhage and microvascular infarcts.[4,5] SLE patients are prone to develop hemorrhagic complications. Spontaneous intracranial hemorrhage is the most serious complication of TP, and is potentially life-threatening. The mechanisms of intracranial hemorrhage are incompletely understood, but several related causes have been summarized,[6] including hypercholesterolemia, hypertension, prolonged treatment with corticosteroids, angiopathy, and aneurysms caused by SLE. Moreover, TP is also an important risk factor. In a single-center retrospective study, 26 out of 6653 SLE cases had intracranial hemorrhage. In these 26 cases, 53.8% had TP, and TP was an independent risk factor for intracranial hemorrhage induced by SLE.[7] That finding is consistent with that of our patient, and the hemorrhages were absorbed while the platelet count returned to normal.
TP treatment in SLE is dependent upon the presentation of systemic disease. Treatment of TP in SLE needs to be specific. Glucocorticoids are regarded as first-line therapy in severe TP but very few patients have sustained remission. IVIG shows rapid, but not long-term, efficacy in patients suffering active bleeding. Hence, immunosuppressive therapy may be warranted.[8] One case of bilateral hemorrhagic retinopathy treated with azathioprine showed the disappearance of Roth spots within 6 weeks of treatment.[9] CSA treatment in patients presenting with TP associated with SLE has shown optimal relief.[10] Broad-spectrum immunosuppressants such as cyclophosphamide have been found to be efficacious in patients with refractory TP in SLE.[11] Some case studies have shown that MMF and tacrolimus can be used to treat TP successfully.[11,12,13] However, some TP patients are refractory to conventional therapies. Biologics could be a good choice for patients with TP in SLE. In a study by Olfat and colleagues,[14] 24 refractory patients with c-SLE were treated with rituximab, of whom 16 had TP, 5 had hemolytic anemia, and 3 had both. Only 1 patient failed to respond to rituximab. All patients tolerated rituximab treatment. However, caution should be exercised when considering rituximab for patients with preexisting hypogammaglobulinemia. According to Lei and colleagues, c-SLE patients intolerant of rituximab who used another B cell-depleting agent, ofatumumab, also obtained a therapeutic effect.[15] Additional treatments, such as plasmapheresis and thrombopoietin receptor agonists, can be efficacious in patients with refractory TP and active bleeding. For some patients with refractory TP non-responsive to medical therapies, splenectomy may be an important alternative.[16] Successful treatment for a-SLE is well documented, but not for c-SLE. Our case had severe TP with potential organ bleeding, so we initiated emergency treatment at an early stage: platelet transfusion, IVIG, mPSL, and CSA. The platelet count fluctuated significantly, so we added MMF which, ultimately, improved TP.
4 Conclusions
Spontaneous subdural hemorrhage with retinal hemorrhage as a consequence of TP in c-SLE is rare. However, we successfully treated our patient with a glucocorticoid combined with 2 immunosuppressants. We consider this regimen to be safe and efficacious treatment in severe TP of c-SLE.
Author contributions
Conceptualization: Ping Lu, Huiling Lu.
Data curation: Ping Lu, Huiling Lu.
Project administration: Yu Wen, Ping Lu, Huiling Lu.
Supervision: Xiufen Hu.
Writing – original draft: Yu Wen.
Writing – review & editing: Yu Wen, Xiufen Hu.
Abbreviations: CSA = cyclosporin-A, c-SLE = childhood-onset systemic lupus erythematous, IVIG = intravenous immunoglobulin, MMF = mycophenolate mofetil, mPSL = methylprednisolone, SLE = systemic lupus erythematosus, TP = thrombocytopenia.
How to cite this article: Wen Y, Lu P, Lu H, Hu X. Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: case report. Medicine. 2021;100:2(e24231).
Written informed consent was obtained from the patient's mother for publication of this case report and accompanying images.
The study protocol was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33466204 | 18,939,623 | 2021-01-15 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: Case report.
BACKGROUND
Thrombocytopenia (TP) is a common complication of childhood-onset systemic lupus erythematosus (SLE), and can range from mild to life-threatening. However, severe TP with multiple hemorrhagic complications is very rare and often predicts a poor prognosis. We describe a 12-year-old Chinese girl who had a history of idiopathic thrombocytopenic purpura who developed SLE that presented as subdural hemorrhage and retinal hemorrhage because of severe TP.
A 12-year-old girl was admitted into our hospital because of fever, purpura, and gum bleeding lasting for 12 days. She had a history of idiopathic thrombocytopenic purpura 2 years ago previously.
METHODS
SLE was diagnosed according to American College of Rheumatology classification criteria. Subdural hemorrhage and retinal hemorrhage were diagnosed based on brain MRI and funduscopy. Severe TP was defined as platelet count <20 × 109/L.
METHODS
She was treated first with intravenous immunoglobulin, but it was not efficacious. High-dose methylprednisolone showed short-term efficacy. Then, she was given a glucocorticoid and cyclosporine A plus mycophenolate mofetil.
RESULTS
Fever, purpura, and gum bleeding were resolved before hospital discharge. Subdural hemorrhage and left hemorrhagic retinopathy were improved remarkably. She had a durable response to refractory TP with no adverse effects during >1-year follow-up.
CONCLUSIONS
Isolated TP may be an early symptom of childhood-onset SLE . A child with severe TP is prone to develop life-threatening hemorrhagic complications. Glucocorticoids and combined immunosuppressive drugs had a durable response to refractory TP in this patient with no adverse effects.
1 Introduction
Systemic lupus erythematosus (SLE) is a multisystem illness. Patients with childhood-onset systemic lupus erythematosus (c-SLE) have a more severe course and organ damage than patients with adult-onset SLE.[1,2] Up to 40% of patients with SLE develop thrombocytopenia (TP). TP is a reliable marker suggesting active disease and often predicts a poor prognosis.[3] Severe TP is relatively uncommon, but it can result in visceral hemorrhage and death.
Although spared from kidney involvement, our pediatric patient developed intracranial and retinal hemorrhages, which were vision-threatening. To date, such a pediatric case has not been reported before.
2 Case report
A 12-year-old girl with a history of idiopathic thrombocytopenic purpura of 2-year duration received intravenous immunoglobulin (IVIG; 1 g/kg bodyweight) treatment for prolonged fever, purpura, gum bleeding, and TP at a local hospital, but showed no response. She developed myalgia, arthralgia, headache, and severe TP (platelet count, 2 × 109/L) lasting for 12 days and was transferred to our hospital.
Upon physical examination, dental ulcers, gum bleeding, purpura on lower extremities, mild hepatomegaly, arthritis on elbow joints, and painless loss of vision in her left eye were noted. Neurological findings appeared normal.
Complete blood cell counts showed a normal white blood cell count (8.28 × 109/L), normocytic normochromic anemia (hemoglobin, 84 g/L) and severe TP (platelet count, 6 × 109/L). Biochemical investigations showed levels of alanine aminotransferase to be 43 U/L, aspartate aminotransferase to be 133 U/L, lactate dehydrogenase to be 800 U/L, and with normal blood urea nitrogen and serum creatinine. Other laboratory findings revealed increased erythrocyte sedimentation rate (117 mm/h), hypocomplementemia (complement C3, 0.4 g/L; complement C4, 0.08 g/L), positivity for serum anti-nuclear antibodies (1:3200), anti-Sm, anti-SS-A, anti-Sm/nRNP, anti-chromatin, anti-RNP 68, anti-RNP A antibodies, and negative for serum anti-dsDNA antibody. The Coombs’ test was 2+, and the patient was negative for antiphospholipid antibody, lupus anticoagulant, and antiplatelet antibody. The activated partial thromboplastin time was 36.6 second, and prothrombin time was 14.2 second.
Urinalyses were normal. Ultrasound of the abdomen revealed hepatosplenomegaly. Subsequent magnetic resonance imaging of the head showed a subacute subdural hemorrhage in bilateral cerebral hemispheres and cerebellum, and multiple demyelinating lesions in the bilateral frontotemporal cortex and bilateral cerebellar hemispheres (Fig. 1A). Funduscopic examination indicated severe retinal hemorrhage in the left eye (Fig. 2A). Based on these data, a diagnosis of severe SLE was established.
Figure 1 Magnetic resonance imaging (MRI) of the brain at different times. (A) Upon presentation, MRI showed a subacute subdural hemorrhage (white arrow) and multiple demyelinating lesions (red arrow) in bilateral cerebral hemispheres and cerebellum. (B) One month later and (C) 4 months later, MRI showed that the subdural hemorrhage had been absorbed completely, and multiple demyelinating lesions became smaller or disappeared in the cerebellum.
Figure 2 Fundus images. (A) Massive retinal hemorrhage on her left eye upon presentation. (B) The retinal hemorrhage on her left eye was absorbed partially after 2 weeks. (C) The retinal hemorrhage on her left eye was absorbed completely after 3 months.
Emergency treatment was initiated with platelet transfusion, IVIG (1 g/kg) and 2 pulses of methylprednisolone (mPSL) with 80 mg/pulse intravenous infusion. Nonetheless, the platelet number failed to increase. On day-3 of hospitalization, she was given high-dose (500 mg) mPSL daily for 3 days followed by high-dose (60 mg/d) prednisolone. The platelet count continued to decrease, so she was also given cyclosporine-A (CSA) (75 mg, q12 hour, p.o.). After intravenous high-dose mPSL, the fever resolved, and the anemia and TP improved. On day-7 of hospitalization, the hemoglobin level increased to 104 g/L, platelet count returned to 197 × 109/L but decreased to 48 × 109/L on day-15. Due to high SLE activity (Systemic Lupus Erythematosus Disease Activity Index was 30) and the very few megakaryocytes in bone marrow (1 megakaryocyte count per slide), she was treated with high-dose (750 mg/d for 4 days) mPSL plus mycophenolate mofetil (MMF). The platelet count continued to fluctuate significantly. Fortunately, her symptoms were much improved. By day-26 of hospitalization, the platelet count began to increase steadily and reached 187 × 109/L on day-42. Then, she was discharged and continued with, CSA, and MMF. Her clinical course in hospital is illustrated in Figure 3.
Figure 3 The clinical course of our patient in hospital.
The subdural hemorrhage (Fig. 1B, C) and left hemorrhagic retinopathy (Fig. 2B and 2C) improved remarkably. Her platelet count decreased to 47 × 109/L because of a respiratory infection 6 months after discharge from hospital, but recovered to 148 × 109/L after 1-week antibiotic treatment. The patient was followed up for >1 year after hospital discharge. The dose of oral drugs was tapered gradually. Relevant side effects did not appear.
3 Discussion
TP is a common manifestation in SLE, and often predicts a poor prognosis. The pathogenesis of TP in SLE is not known. The presumed mechanisms include: platelet destruction and deletion by autoantibodies in the peripheral circulation; inhibition of the development and maturation of megakaryocytes in bone marrow; consumption of platelets because of thrombotic microangiopathy/thrombotic thrombocytopenic purpura (TTP); secondary antiphospholipid syndrome (APS). These mechanisms often coexist.[3] Inhibition of the development and maturation of megakaryocytes in bone marrow is an important factor. Zhao et al[3] reported that patients with a megakaryocyte count in bone marrow <20/slide have a poor clinical response to immunotherapy. In our case, the megakaryocyte number decreased significantly, with 1 megakaryocyte count per slide justifying that TP was refractory to immunotherapy.
Retinal hemorrhage and subdural hemorrhage occurring together are unusual in SLE (especially in c-SLE). About one-third of SLE patients develop ocular manifestations, with 7% to 29% showing retinal involvement. Retinopathy is probably caused by “cotton wool” spots, retinal haemorrhage and microvascular infarcts.[4,5] SLE patients are prone to develop hemorrhagic complications. Spontaneous intracranial hemorrhage is the most serious complication of TP, and is potentially life-threatening. The mechanisms of intracranial hemorrhage are incompletely understood, but several related causes have been summarized,[6] including hypercholesterolemia, hypertension, prolonged treatment with corticosteroids, angiopathy, and aneurysms caused by SLE. Moreover, TP is also an important risk factor. In a single-center retrospective study, 26 out of 6653 SLE cases had intracranial hemorrhage. In these 26 cases, 53.8% had TP, and TP was an independent risk factor for intracranial hemorrhage induced by SLE.[7] That finding is consistent with that of our patient, and the hemorrhages were absorbed while the platelet count returned to normal.
TP treatment in SLE is dependent upon the presentation of systemic disease. Treatment of TP in SLE needs to be specific. Glucocorticoids are regarded as first-line therapy in severe TP but very few patients have sustained remission. IVIG shows rapid, but not long-term, efficacy in patients suffering active bleeding. Hence, immunosuppressive therapy may be warranted.[8] One case of bilateral hemorrhagic retinopathy treated with azathioprine showed the disappearance of Roth spots within 6 weeks of treatment.[9] CSA treatment in patients presenting with TP associated with SLE has shown optimal relief.[10] Broad-spectrum immunosuppressants such as cyclophosphamide have been found to be efficacious in patients with refractory TP in SLE.[11] Some case studies have shown that MMF and tacrolimus can be used to treat TP successfully.[11,12,13] However, some TP patients are refractory to conventional therapies. Biologics could be a good choice for patients with TP in SLE. In a study by Olfat and colleagues,[14] 24 refractory patients with c-SLE were treated with rituximab, of whom 16 had TP, 5 had hemolytic anemia, and 3 had both. Only 1 patient failed to respond to rituximab. All patients tolerated rituximab treatment. However, caution should be exercised when considering rituximab for patients with preexisting hypogammaglobulinemia. According to Lei and colleagues, c-SLE patients intolerant of rituximab who used another B cell-depleting agent, ofatumumab, also obtained a therapeutic effect.[15] Additional treatments, such as plasmapheresis and thrombopoietin receptor agonists, can be efficacious in patients with refractory TP and active bleeding. For some patients with refractory TP non-responsive to medical therapies, splenectomy may be an important alternative.[16] Successful treatment for a-SLE is well documented, but not for c-SLE. Our case had severe TP with potential organ bleeding, so we initiated emergency treatment at an early stage: platelet transfusion, IVIG, mPSL, and CSA. The platelet count fluctuated significantly, so we added MMF which, ultimately, improved TP.
4 Conclusions
Spontaneous subdural hemorrhage with retinal hemorrhage as a consequence of TP in c-SLE is rare. However, we successfully treated our patient with a glucocorticoid combined with 2 immunosuppressants. We consider this regimen to be safe and efficacious treatment in severe TP of c-SLE.
Author contributions
Conceptualization: Ping Lu, Huiling Lu.
Data curation: Ping Lu, Huiling Lu.
Project administration: Yu Wen, Ping Lu, Huiling Lu.
Supervision: Xiufen Hu.
Writing – original draft: Yu Wen.
Writing – review & editing: Yu Wen, Xiufen Hu.
Abbreviations: CSA = cyclosporin-A, c-SLE = childhood-onset systemic lupus erythematous, IVIG = intravenous immunoglobulin, MMF = mycophenolate mofetil, mPSL = methylprednisolone, SLE = systemic lupus erythematosus, TP = thrombocytopenia.
How to cite this article: Wen Y, Lu P, Lu H, Hu X. Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: case report. Medicine. 2021;100:2(e24231).
Written informed consent was obtained from the patient's mother for publication of this case report and accompanying images.
The study protocol was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33466204 | 18,939,623 | 2021-01-15 |
What was the outcome of reaction 'Drug ineffective'? | Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: Case report.
BACKGROUND
Thrombocytopenia (TP) is a common complication of childhood-onset systemic lupus erythematosus (SLE), and can range from mild to life-threatening. However, severe TP with multiple hemorrhagic complications is very rare and often predicts a poor prognosis. We describe a 12-year-old Chinese girl who had a history of idiopathic thrombocytopenic purpura who developed SLE that presented as subdural hemorrhage and retinal hemorrhage because of severe TP.
A 12-year-old girl was admitted into our hospital because of fever, purpura, and gum bleeding lasting for 12 days. She had a history of idiopathic thrombocytopenic purpura 2 years ago previously.
METHODS
SLE was diagnosed according to American College of Rheumatology classification criteria. Subdural hemorrhage and retinal hemorrhage were diagnosed based on brain MRI and funduscopy. Severe TP was defined as platelet count <20 × 109/L.
METHODS
She was treated first with intravenous immunoglobulin, but it was not efficacious. High-dose methylprednisolone showed short-term efficacy. Then, she was given a glucocorticoid and cyclosporine A plus mycophenolate mofetil.
RESULTS
Fever, purpura, and gum bleeding were resolved before hospital discharge. Subdural hemorrhage and left hemorrhagic retinopathy were improved remarkably. She had a durable response to refractory TP with no adverse effects during >1-year follow-up.
CONCLUSIONS
Isolated TP may be an early symptom of childhood-onset SLE . A child with severe TP is prone to develop life-threatening hemorrhagic complications. Glucocorticoids and combined immunosuppressive drugs had a durable response to refractory TP in this patient with no adverse effects.
1 Introduction
Systemic lupus erythematosus (SLE) is a multisystem illness. Patients with childhood-onset systemic lupus erythematosus (c-SLE) have a more severe course and organ damage than patients with adult-onset SLE.[1,2] Up to 40% of patients with SLE develop thrombocytopenia (TP). TP is a reliable marker suggesting active disease and often predicts a poor prognosis.[3] Severe TP is relatively uncommon, but it can result in visceral hemorrhage and death.
Although spared from kidney involvement, our pediatric patient developed intracranial and retinal hemorrhages, which were vision-threatening. To date, such a pediatric case has not been reported before.
2 Case report
A 12-year-old girl with a history of idiopathic thrombocytopenic purpura of 2-year duration received intravenous immunoglobulin (IVIG; 1 g/kg bodyweight) treatment for prolonged fever, purpura, gum bleeding, and TP at a local hospital, but showed no response. She developed myalgia, arthralgia, headache, and severe TP (platelet count, 2 × 109/L) lasting for 12 days and was transferred to our hospital.
Upon physical examination, dental ulcers, gum bleeding, purpura on lower extremities, mild hepatomegaly, arthritis on elbow joints, and painless loss of vision in her left eye were noted. Neurological findings appeared normal.
Complete blood cell counts showed a normal white blood cell count (8.28 × 109/L), normocytic normochromic anemia (hemoglobin, 84 g/L) and severe TP (platelet count, 6 × 109/L). Biochemical investigations showed levels of alanine aminotransferase to be 43 U/L, aspartate aminotransferase to be 133 U/L, lactate dehydrogenase to be 800 U/L, and with normal blood urea nitrogen and serum creatinine. Other laboratory findings revealed increased erythrocyte sedimentation rate (117 mm/h), hypocomplementemia (complement C3, 0.4 g/L; complement C4, 0.08 g/L), positivity for serum anti-nuclear antibodies (1:3200), anti-Sm, anti-SS-A, anti-Sm/nRNP, anti-chromatin, anti-RNP 68, anti-RNP A antibodies, and negative for serum anti-dsDNA antibody. The Coombs’ test was 2+, and the patient was negative for antiphospholipid antibody, lupus anticoagulant, and antiplatelet antibody. The activated partial thromboplastin time was 36.6 second, and prothrombin time was 14.2 second.
Urinalyses were normal. Ultrasound of the abdomen revealed hepatosplenomegaly. Subsequent magnetic resonance imaging of the head showed a subacute subdural hemorrhage in bilateral cerebral hemispheres and cerebellum, and multiple demyelinating lesions in the bilateral frontotemporal cortex and bilateral cerebellar hemispheres (Fig. 1A). Funduscopic examination indicated severe retinal hemorrhage in the left eye (Fig. 2A). Based on these data, a diagnosis of severe SLE was established.
Figure 1 Magnetic resonance imaging (MRI) of the brain at different times. (A) Upon presentation, MRI showed a subacute subdural hemorrhage (white arrow) and multiple demyelinating lesions (red arrow) in bilateral cerebral hemispheres and cerebellum. (B) One month later and (C) 4 months later, MRI showed that the subdural hemorrhage had been absorbed completely, and multiple demyelinating lesions became smaller or disappeared in the cerebellum.
Figure 2 Fundus images. (A) Massive retinal hemorrhage on her left eye upon presentation. (B) The retinal hemorrhage on her left eye was absorbed partially after 2 weeks. (C) The retinal hemorrhage on her left eye was absorbed completely after 3 months.
Emergency treatment was initiated with platelet transfusion, IVIG (1 g/kg) and 2 pulses of methylprednisolone (mPSL) with 80 mg/pulse intravenous infusion. Nonetheless, the platelet number failed to increase. On day-3 of hospitalization, she was given high-dose (500 mg) mPSL daily for 3 days followed by high-dose (60 mg/d) prednisolone. The platelet count continued to decrease, so she was also given cyclosporine-A (CSA) (75 mg, q12 hour, p.o.). After intravenous high-dose mPSL, the fever resolved, and the anemia and TP improved. On day-7 of hospitalization, the hemoglobin level increased to 104 g/L, platelet count returned to 197 × 109/L but decreased to 48 × 109/L on day-15. Due to high SLE activity (Systemic Lupus Erythematosus Disease Activity Index was 30) and the very few megakaryocytes in bone marrow (1 megakaryocyte count per slide), she was treated with high-dose (750 mg/d for 4 days) mPSL plus mycophenolate mofetil (MMF). The platelet count continued to fluctuate significantly. Fortunately, her symptoms were much improved. By day-26 of hospitalization, the platelet count began to increase steadily and reached 187 × 109/L on day-42. Then, she was discharged and continued with, CSA, and MMF. Her clinical course in hospital is illustrated in Figure 3.
Figure 3 The clinical course of our patient in hospital.
The subdural hemorrhage (Fig. 1B, C) and left hemorrhagic retinopathy (Fig. 2B and 2C) improved remarkably. Her platelet count decreased to 47 × 109/L because of a respiratory infection 6 months after discharge from hospital, but recovered to 148 × 109/L after 1-week antibiotic treatment. The patient was followed up for >1 year after hospital discharge. The dose of oral drugs was tapered gradually. Relevant side effects did not appear.
3 Discussion
TP is a common manifestation in SLE, and often predicts a poor prognosis. The pathogenesis of TP in SLE is not known. The presumed mechanisms include: platelet destruction and deletion by autoantibodies in the peripheral circulation; inhibition of the development and maturation of megakaryocytes in bone marrow; consumption of platelets because of thrombotic microangiopathy/thrombotic thrombocytopenic purpura (TTP); secondary antiphospholipid syndrome (APS). These mechanisms often coexist.[3] Inhibition of the development and maturation of megakaryocytes in bone marrow is an important factor. Zhao et al[3] reported that patients with a megakaryocyte count in bone marrow <20/slide have a poor clinical response to immunotherapy. In our case, the megakaryocyte number decreased significantly, with 1 megakaryocyte count per slide justifying that TP was refractory to immunotherapy.
Retinal hemorrhage and subdural hemorrhage occurring together are unusual in SLE (especially in c-SLE). About one-third of SLE patients develop ocular manifestations, with 7% to 29% showing retinal involvement. Retinopathy is probably caused by “cotton wool” spots, retinal haemorrhage and microvascular infarcts.[4,5] SLE patients are prone to develop hemorrhagic complications. Spontaneous intracranial hemorrhage is the most serious complication of TP, and is potentially life-threatening. The mechanisms of intracranial hemorrhage are incompletely understood, but several related causes have been summarized,[6] including hypercholesterolemia, hypertension, prolonged treatment with corticosteroids, angiopathy, and aneurysms caused by SLE. Moreover, TP is also an important risk factor. In a single-center retrospective study, 26 out of 6653 SLE cases had intracranial hemorrhage. In these 26 cases, 53.8% had TP, and TP was an independent risk factor for intracranial hemorrhage induced by SLE.[7] That finding is consistent with that of our patient, and the hemorrhages were absorbed while the platelet count returned to normal.
TP treatment in SLE is dependent upon the presentation of systemic disease. Treatment of TP in SLE needs to be specific. Glucocorticoids are regarded as first-line therapy in severe TP but very few patients have sustained remission. IVIG shows rapid, but not long-term, efficacy in patients suffering active bleeding. Hence, immunosuppressive therapy may be warranted.[8] One case of bilateral hemorrhagic retinopathy treated with azathioprine showed the disappearance of Roth spots within 6 weeks of treatment.[9] CSA treatment in patients presenting with TP associated with SLE has shown optimal relief.[10] Broad-spectrum immunosuppressants such as cyclophosphamide have been found to be efficacious in patients with refractory TP in SLE.[11] Some case studies have shown that MMF and tacrolimus can be used to treat TP successfully.[11,12,13] However, some TP patients are refractory to conventional therapies. Biologics could be a good choice for patients with TP in SLE. In a study by Olfat and colleagues,[14] 24 refractory patients with c-SLE were treated with rituximab, of whom 16 had TP, 5 had hemolytic anemia, and 3 had both. Only 1 patient failed to respond to rituximab. All patients tolerated rituximab treatment. However, caution should be exercised when considering rituximab for patients with preexisting hypogammaglobulinemia. According to Lei and colleagues, c-SLE patients intolerant of rituximab who used another B cell-depleting agent, ofatumumab, also obtained a therapeutic effect.[15] Additional treatments, such as plasmapheresis and thrombopoietin receptor agonists, can be efficacious in patients with refractory TP and active bleeding. For some patients with refractory TP non-responsive to medical therapies, splenectomy may be an important alternative.[16] Successful treatment for a-SLE is well documented, but not for c-SLE. Our case had severe TP with potential organ bleeding, so we initiated emergency treatment at an early stage: platelet transfusion, IVIG, mPSL, and CSA. The platelet count fluctuated significantly, so we added MMF which, ultimately, improved TP.
4 Conclusions
Spontaneous subdural hemorrhage with retinal hemorrhage as a consequence of TP in c-SLE is rare. However, we successfully treated our patient with a glucocorticoid combined with 2 immunosuppressants. We consider this regimen to be safe and efficacious treatment in severe TP of c-SLE.
Author contributions
Conceptualization: Ping Lu, Huiling Lu.
Data curation: Ping Lu, Huiling Lu.
Project administration: Yu Wen, Ping Lu, Huiling Lu.
Supervision: Xiufen Hu.
Writing – original draft: Yu Wen.
Writing – review & editing: Yu Wen, Xiufen Hu.
Abbreviations: CSA = cyclosporin-A, c-SLE = childhood-onset systemic lupus erythematous, IVIG = intravenous immunoglobulin, MMF = mycophenolate mofetil, mPSL = methylprednisolone, SLE = systemic lupus erythematosus, TP = thrombocytopenia.
How to cite this article: Wen Y, Lu P, Lu H, Hu X. Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: case report. Medicine. 2021;100:2(e24231).
Written informed consent was obtained from the patient's mother for publication of this case report and accompanying images.
The study protocol was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Recovered | ReactionOutcome | CC BY | 33466204 | 18,939,623 | 2021-01-15 |
What was the outcome of reaction 'Thrombocytopenia'? | Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: Case report.
BACKGROUND
Thrombocytopenia (TP) is a common complication of childhood-onset systemic lupus erythematosus (SLE), and can range from mild to life-threatening. However, severe TP with multiple hemorrhagic complications is very rare and often predicts a poor prognosis. We describe a 12-year-old Chinese girl who had a history of idiopathic thrombocytopenic purpura who developed SLE that presented as subdural hemorrhage and retinal hemorrhage because of severe TP.
A 12-year-old girl was admitted into our hospital because of fever, purpura, and gum bleeding lasting for 12 days. She had a history of idiopathic thrombocytopenic purpura 2 years ago previously.
METHODS
SLE was diagnosed according to American College of Rheumatology classification criteria. Subdural hemorrhage and retinal hemorrhage were diagnosed based on brain MRI and funduscopy. Severe TP was defined as platelet count <20 × 109/L.
METHODS
She was treated first with intravenous immunoglobulin, but it was not efficacious. High-dose methylprednisolone showed short-term efficacy. Then, she was given a glucocorticoid and cyclosporine A plus mycophenolate mofetil.
RESULTS
Fever, purpura, and gum bleeding were resolved before hospital discharge. Subdural hemorrhage and left hemorrhagic retinopathy were improved remarkably. She had a durable response to refractory TP with no adverse effects during >1-year follow-up.
CONCLUSIONS
Isolated TP may be an early symptom of childhood-onset SLE . A child with severe TP is prone to develop life-threatening hemorrhagic complications. Glucocorticoids and combined immunosuppressive drugs had a durable response to refractory TP in this patient with no adverse effects.
1 Introduction
Systemic lupus erythematosus (SLE) is a multisystem illness. Patients with childhood-onset systemic lupus erythematosus (c-SLE) have a more severe course and organ damage than patients with adult-onset SLE.[1,2] Up to 40% of patients with SLE develop thrombocytopenia (TP). TP is a reliable marker suggesting active disease and often predicts a poor prognosis.[3] Severe TP is relatively uncommon, but it can result in visceral hemorrhage and death.
Although spared from kidney involvement, our pediatric patient developed intracranial and retinal hemorrhages, which were vision-threatening. To date, such a pediatric case has not been reported before.
2 Case report
A 12-year-old girl with a history of idiopathic thrombocytopenic purpura of 2-year duration received intravenous immunoglobulin (IVIG; 1 g/kg bodyweight) treatment for prolonged fever, purpura, gum bleeding, and TP at a local hospital, but showed no response. She developed myalgia, arthralgia, headache, and severe TP (platelet count, 2 × 109/L) lasting for 12 days and was transferred to our hospital.
Upon physical examination, dental ulcers, gum bleeding, purpura on lower extremities, mild hepatomegaly, arthritis on elbow joints, and painless loss of vision in her left eye were noted. Neurological findings appeared normal.
Complete blood cell counts showed a normal white blood cell count (8.28 × 109/L), normocytic normochromic anemia (hemoglobin, 84 g/L) and severe TP (platelet count, 6 × 109/L). Biochemical investigations showed levels of alanine aminotransferase to be 43 U/L, aspartate aminotransferase to be 133 U/L, lactate dehydrogenase to be 800 U/L, and with normal blood urea nitrogen and serum creatinine. Other laboratory findings revealed increased erythrocyte sedimentation rate (117 mm/h), hypocomplementemia (complement C3, 0.4 g/L; complement C4, 0.08 g/L), positivity for serum anti-nuclear antibodies (1:3200), anti-Sm, anti-SS-A, anti-Sm/nRNP, anti-chromatin, anti-RNP 68, anti-RNP A antibodies, and negative for serum anti-dsDNA antibody. The Coombs’ test was 2+, and the patient was negative for antiphospholipid antibody, lupus anticoagulant, and antiplatelet antibody. The activated partial thromboplastin time was 36.6 second, and prothrombin time was 14.2 second.
Urinalyses were normal. Ultrasound of the abdomen revealed hepatosplenomegaly. Subsequent magnetic resonance imaging of the head showed a subacute subdural hemorrhage in bilateral cerebral hemispheres and cerebellum, and multiple demyelinating lesions in the bilateral frontotemporal cortex and bilateral cerebellar hemispheres (Fig. 1A). Funduscopic examination indicated severe retinal hemorrhage in the left eye (Fig. 2A). Based on these data, a diagnosis of severe SLE was established.
Figure 1 Magnetic resonance imaging (MRI) of the brain at different times. (A) Upon presentation, MRI showed a subacute subdural hemorrhage (white arrow) and multiple demyelinating lesions (red arrow) in bilateral cerebral hemispheres and cerebellum. (B) One month later and (C) 4 months later, MRI showed that the subdural hemorrhage had been absorbed completely, and multiple demyelinating lesions became smaller or disappeared in the cerebellum.
Figure 2 Fundus images. (A) Massive retinal hemorrhage on her left eye upon presentation. (B) The retinal hemorrhage on her left eye was absorbed partially after 2 weeks. (C) The retinal hemorrhage on her left eye was absorbed completely after 3 months.
Emergency treatment was initiated with platelet transfusion, IVIG (1 g/kg) and 2 pulses of methylprednisolone (mPSL) with 80 mg/pulse intravenous infusion. Nonetheless, the platelet number failed to increase. On day-3 of hospitalization, she was given high-dose (500 mg) mPSL daily for 3 days followed by high-dose (60 mg/d) prednisolone. The platelet count continued to decrease, so she was also given cyclosporine-A (CSA) (75 mg, q12 hour, p.o.). After intravenous high-dose mPSL, the fever resolved, and the anemia and TP improved. On day-7 of hospitalization, the hemoglobin level increased to 104 g/L, platelet count returned to 197 × 109/L but decreased to 48 × 109/L on day-15. Due to high SLE activity (Systemic Lupus Erythematosus Disease Activity Index was 30) and the very few megakaryocytes in bone marrow (1 megakaryocyte count per slide), she was treated with high-dose (750 mg/d for 4 days) mPSL plus mycophenolate mofetil (MMF). The platelet count continued to fluctuate significantly. Fortunately, her symptoms were much improved. By day-26 of hospitalization, the platelet count began to increase steadily and reached 187 × 109/L on day-42. Then, she was discharged and continued with, CSA, and MMF. Her clinical course in hospital is illustrated in Figure 3.
Figure 3 The clinical course of our patient in hospital.
The subdural hemorrhage (Fig. 1B, C) and left hemorrhagic retinopathy (Fig. 2B and 2C) improved remarkably. Her platelet count decreased to 47 × 109/L because of a respiratory infection 6 months after discharge from hospital, but recovered to 148 × 109/L after 1-week antibiotic treatment. The patient was followed up for >1 year after hospital discharge. The dose of oral drugs was tapered gradually. Relevant side effects did not appear.
3 Discussion
TP is a common manifestation in SLE, and often predicts a poor prognosis. The pathogenesis of TP in SLE is not known. The presumed mechanisms include: platelet destruction and deletion by autoantibodies in the peripheral circulation; inhibition of the development and maturation of megakaryocytes in bone marrow; consumption of platelets because of thrombotic microangiopathy/thrombotic thrombocytopenic purpura (TTP); secondary antiphospholipid syndrome (APS). These mechanisms often coexist.[3] Inhibition of the development and maturation of megakaryocytes in bone marrow is an important factor. Zhao et al[3] reported that patients with a megakaryocyte count in bone marrow <20/slide have a poor clinical response to immunotherapy. In our case, the megakaryocyte number decreased significantly, with 1 megakaryocyte count per slide justifying that TP was refractory to immunotherapy.
Retinal hemorrhage and subdural hemorrhage occurring together are unusual in SLE (especially in c-SLE). About one-third of SLE patients develop ocular manifestations, with 7% to 29% showing retinal involvement. Retinopathy is probably caused by “cotton wool” spots, retinal haemorrhage and microvascular infarcts.[4,5] SLE patients are prone to develop hemorrhagic complications. Spontaneous intracranial hemorrhage is the most serious complication of TP, and is potentially life-threatening. The mechanisms of intracranial hemorrhage are incompletely understood, but several related causes have been summarized,[6] including hypercholesterolemia, hypertension, prolonged treatment with corticosteroids, angiopathy, and aneurysms caused by SLE. Moreover, TP is also an important risk factor. In a single-center retrospective study, 26 out of 6653 SLE cases had intracranial hemorrhage. In these 26 cases, 53.8% had TP, and TP was an independent risk factor for intracranial hemorrhage induced by SLE.[7] That finding is consistent with that of our patient, and the hemorrhages were absorbed while the platelet count returned to normal.
TP treatment in SLE is dependent upon the presentation of systemic disease. Treatment of TP in SLE needs to be specific. Glucocorticoids are regarded as first-line therapy in severe TP but very few patients have sustained remission. IVIG shows rapid, but not long-term, efficacy in patients suffering active bleeding. Hence, immunosuppressive therapy may be warranted.[8] One case of bilateral hemorrhagic retinopathy treated with azathioprine showed the disappearance of Roth spots within 6 weeks of treatment.[9] CSA treatment in patients presenting with TP associated with SLE has shown optimal relief.[10] Broad-spectrum immunosuppressants such as cyclophosphamide have been found to be efficacious in patients with refractory TP in SLE.[11] Some case studies have shown that MMF and tacrolimus can be used to treat TP successfully.[11,12,13] However, some TP patients are refractory to conventional therapies. Biologics could be a good choice for patients with TP in SLE. In a study by Olfat and colleagues,[14] 24 refractory patients with c-SLE were treated with rituximab, of whom 16 had TP, 5 had hemolytic anemia, and 3 had both. Only 1 patient failed to respond to rituximab. All patients tolerated rituximab treatment. However, caution should be exercised when considering rituximab for patients with preexisting hypogammaglobulinemia. According to Lei and colleagues, c-SLE patients intolerant of rituximab who used another B cell-depleting agent, ofatumumab, also obtained a therapeutic effect.[15] Additional treatments, such as plasmapheresis and thrombopoietin receptor agonists, can be efficacious in patients with refractory TP and active bleeding. For some patients with refractory TP non-responsive to medical therapies, splenectomy may be an important alternative.[16] Successful treatment for a-SLE is well documented, but not for c-SLE. Our case had severe TP with potential organ bleeding, so we initiated emergency treatment at an early stage: platelet transfusion, IVIG, mPSL, and CSA. The platelet count fluctuated significantly, so we added MMF which, ultimately, improved TP.
4 Conclusions
Spontaneous subdural hemorrhage with retinal hemorrhage as a consequence of TP in c-SLE is rare. However, we successfully treated our patient with a glucocorticoid combined with 2 immunosuppressants. We consider this regimen to be safe and efficacious treatment in severe TP of c-SLE.
Author contributions
Conceptualization: Ping Lu, Huiling Lu.
Data curation: Ping Lu, Huiling Lu.
Project administration: Yu Wen, Ping Lu, Huiling Lu.
Supervision: Xiufen Hu.
Writing – original draft: Yu Wen.
Writing – review & editing: Yu Wen, Xiufen Hu.
Abbreviations: CSA = cyclosporin-A, c-SLE = childhood-onset systemic lupus erythematous, IVIG = intravenous immunoglobulin, MMF = mycophenolate mofetil, mPSL = methylprednisolone, SLE = systemic lupus erythematosus, TP = thrombocytopenia.
How to cite this article: Wen Y, Lu P, Lu H, Hu X. Successful treatment of subdural hemorrhage and retinal hemorrhage in childhood-onset systemic lupus erythematosus associated with thrombocytopenia: case report. Medicine. 2021;100:2(e24231).
Written informed consent was obtained from the patient's mother for publication of this case report and accompanying images.
The study protocol was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | Recovered | ReactionOutcome | CC BY | 33466204 | 18,939,623 | 2021-01-15 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Achromobacter infection'. | A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient.
Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient's respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.
1. Case Presentation
We report the case of a 12-year-old boy (35.5 kg), who received double lung transplantation in 25 March 2017, (at the age of 12) because of cystic fibrosis. Before transplantation, he was colonized with Aspergillus fumigatus, Achromobacter xylosoxidans (first colonization identified in 2013), and Pseudomonas aeruginosa. After transplantation, he experienced acute kidney injury requiring temporary haemodialysis, pulmonary embolism, and persisting airway colonization with A. fumigatus. He was discharged on 29 April 2017, with satisfactory respiratory status; he initially required no home oxygen therapy. His immunosuppressive regimen included prednisolone (25 mg/day), tacrolimus (1.5 mg bis in die (b.i.d.) with a target trough concentration of 6–8 ng/mL), mycophenolate mofetil (1 g b.i.d.) and his antimicrobial prophylaxis was cotrimoxazole (400/80 mg, three times a week), posaconazole (150 mg, oral suspension, ter in die (t.i.d.)), valacyclovir (500 mg b.i.d.), and intravenous immunoglobulins (15 g each three weeks).
Between May and June 2017, he experienced progressive shortness of breath, cough and increased sputum production; he subsequently required the addition of 1–1.5 L/min oxygen therapy. Because of a stenosis of the surgical anastomosis of the main left bronchus, a dilatation during rigid bronchoscopy was performed on 19 May and a Montgomery stent was inserted on 2 June. Later on, a stenosis of the surgical anastomosis on the right bronchus intermedius required a dilatation during rigid bronchoscopy followed by the insertion of an Oki stent on 29 June.
Several bronchoalveolar lavages (BAL), performed between May and June 2017, revealed inflammation (between 800 and >1000 leukocytes/mm3 with 88–90% of polymorphonuclear cells) and repeatedly grew pandrug-resistant A. xylosoxidans (Table 1 and Supplementary Figure S1) [1]. Lung biopsy performed on 19 June was consistent with lung infection: diffuse acute bronchiolitis with extension to peri-bronchiolar alveoli. Microbiological samples obtained from lung biopsies were negative (bacterial, mycological, and mycobacteriological cultures). The first antibiotic treatment consisted of intravenous tigecycline 50 mg b.i.d. from 29 June to 31 July. As BAL remained positive for A. xylosoxidans and the patient still required oxygen therapy; antibiotic treatment was subsequently switched to imipenem (1200 mg, t.i.d., ~100 mg/Kg/d) on 31 July 2017. Subsequent respiratory samples still grew A. xylosoxidans and the respiratory status did not improve (requiring oxygen at home, 1 L/min). Furthermore, despite antibiotic treatment and correct drainage of the right superior lobe, lung consolidation and micronodules remained.
Considering the failure of antibiotic treatment, phage therapy was proposed to the patient and his family, after multidisciplinary discussion. A first cocktail (APC 1.1) containing three lytic phages (JWDelta, JWT and 2-1) active against A. xylosoxidans isolate is1S (designated such as later), selected from the DSMZ collection (Braunschweig, Germany) [2,3], was prepared at the Laboratory for Bacteriology Research (Ghent University, Belgium) and the Laboratory for Molecular and Cellular Technology (Queen Astrid Military Hospital, Brussels, Belgium) using the above-mentioned bacterial isolate, as previously described [4]. The production was completed on 23 August with a final phage titer of 4 × 1010 plaque forming units (pfu)/mL defined by double-agar overlay method [4], an endotoxin level of 4000 EU/mL (ToxinSensor Chromogenic LAL Endotoxin Assay Kit, GenScript, Piscataway Township, NJ, USA) and a pH of 7.3 (in sterile PBS). Regulatory permission for phage importation was obtained on 1 September 2017, from the Agence Nationale de Sécurité du Médicament (ANSM). A first round of phage administration was performed, consisting of 3 nebulizations/day of 5 mL of the filter-sterilized (Sartorius 0.2 µm) phage solution, tenfold diluted in sterile saline on 8 and 9 September, using a vibrating mesh nebulizer (eFLOW rapid, PARI, PARI GmbH, Germany) with a mouth piece. Immediate tolerance was perfect, but no clinical improvement was noted and culture of subsequent respiratory samples remained positive for A. xylosoxidans (104 CFU/mL in the BAL of 15 September).
A second cocktail (APC 2.1) was produced, in which phage JWalpha was added to the three lytic phages of cocktail APC 1.1, to improve the therapeutic efficacy. The production was completed on 22 December with a final phage titer of 5 × 109 pfu/mL, an endotoxin level of 1760 EU/mL and a pH of 6.95 (in sterile PBS). Regulatory permission was obtained for phage importation on 16 January 2018 (ANSM). On 23 January, during therapeutic bronchoscopy under general anesthesia, 30 mL of APC2.1, tenfold diluted (in sterile saline) and filter-sterilized, was instilled in each pulmonary lobe through the fibroscope. Immediate tolerance was perfect and the patient was discharged on 24 January with continued phage nebulization at home: three times a day 5 mL of preparation A using a vibrating mesh nebulizer (eFLOW rapid, PARI) with a mouth piece for 14 days until 6 February. Clinical tolerance was perfect again, but the initial clinical status remained unchanged. BAL performed on 8 February 2018, two days after stopping the phage treatment, still grew 105 cfu/mL of A. xylosoxidans. Subsequently, the patient’s respiratory condition slowly improved and oxygen therapy was stopped on 15 February 2018. No clinical worsening was observed after imipenem interruption on 16 February 2018. Sputum culture remained positive for A. xylosoxidans but with a low bacterial density (103 CFU/mL in March and May 2018, and June 2019) and no A. xylosoxidans could be isolated from BALs#10 and #11, sampled on August 2019, and April 2020, respectively (Table 1). The last pulmonary function tests, performed on 17 October 2019, showed best results since lung transplantation, with an FEV1 of 79% and a forced vital capacity of 85%.
2. Microbiological Analysis of Eight A. xylosoxidans Isolates
As we observed discrepant outcome in our patient (clinical improvement on the one hand but persisting low-grade airway colonization on the other hand), we decided to study the eight available A. xylosoxidans isolates (is1 to is9) from the patient’s colonization obtained by random picking from the culture plates from 4 distinct BALs (Table 2). These eight isolates, taken before, during and after the phage therapy period (Table 2), could not be differentiated from each other by means of MALDI-TOF [5] or McRAPD typing [6] and all belonged to the epidemic clone, already described previously among Belgian CF patients [5]. Whole genome sequencing (WGS) and de novo genome assembly for these eight isolates was carried out (Supplementary Methods and Table S1). The sequencing reads and genome sequences of all isolates have been submitted to the European Nucleotide Archive (ENA) and are available under project number PRJEB39103 (Table 2). (https://www.ebi.ac.uk/ena/browser/view/PRJEB39103).
Total genome length for all eight isolates was 6.44–6.50 Mbp, with a GC content of 67.5%. All eight isolates showed most similarity with reference genome GCF_008432465 (AX1), which corresponds to the type strain of A. xylosoxidans subsp. xylosoxidans (ATCC 27061T, CCUG 12689T, DSMZ 10346T, LMG 1863T, and NCTC 10807T), i.e., between 88.38 and 89.60% on the basis of mapped sequence reads, and between 98.71% and 98.76% on the basis of average nucleotide identity (ANI). Indeed, the overall similarity between the genome sequences of the eight isolates was high, i.e., 99.60%, as assessed by digital DNA hybridization, and more than 99.97% according to ANI-analysis. This was confirmed by variant calling where we observed that the isolates differed from each other only for a total of 367 SNPs, whereas a total of 59,452 SNPs were observed between the isolates and the best matching reference genome (AX1) (Figure 1). The susceptibility phenotype of each of the eight isolates was assessed by spot-test against the phage cocktail APC 2.1 and expressed as “S” when susceptible or “R” when resistant (e.g., “is2S” means that isolate number 2 was susceptible to the phage cocktail) (Table 2 and Supplementary Methods). Among these eight isolates, analysis based on variant calling furthermore revealed four closely related but clearly delineated strains, i.e., clones that differ genetically from other clones, with different phage susceptibility phenotype (Table 2 and Figure 1): Strain 1 (Str1), contained isolates 1 and 3 (is1S and is3R), found in BAL#3 (is1S-Str1/BAL#3) and BAL#5 (is3R-Str1/BAL#5), respectively. Strain 2 (Str2) contained isolate 2 (is2S) from BAL#5 (is2S-Str2/BAL#5). Strain 3 (Str3) contained isolates 5, 6, and 9 (is5S, is6S and is9S), which were found in BAL#6 (is5S-Str3/BAL#6, is6S-Str3/BAL#6) and BAL#9 (is9S-Str3/BAL#9). Strain 4 contained isolates 7 and 8 (is7R and is8R), found in BAL#9 (is7R-Str4/BAL#9 and is8R-Str4/BAL#9) (Table 2).
Isolate is1S-Str1/BAL#3 was obtained on 25 July 2017, i.e., 45 days before the first phage therapy session (8 September 2017) and was 100% identical to is3R-Str1/BAL#5 isolated seven days (15 September 2017) after the first phage therapy session (Figure 1). Since both isolates is1S-Str1/BAL#3 and is3R-Str1/BAL#5 are 100% identical, this means that the phage resistance mechanism of isolate is3R-Str1/BAL#5 is not genetically supported (see discussion). Isolates is5S-Str3/BAL#6 and is6S-Str3/BAL#6, both phage susceptible, were obtained one month later (12 October 2017) and belonged to still another strain (Strain 3). Finally, on 8 February 2018, i.e., 16 days after the second phage therapy session (23 January 2018), an additional three isolates were obtained from BAL#9. Of these, isolate is9S-Str3/BAL#9 belonged to the same Strain 3 as isolates is5S-Str3/BAL#6 and is6S-Str3/BAL#6 and was phage susceptible as well, but isolates 7R and 8R belonged to still another strain (Strain 4) and were both resistant to the phage cocktail. Interestingly, the phage resistant Strain 4 isolates (is7R-Str4/BAL#9 and is8R-Str4/BAL#9) contained mutations compared to the other six isolates that could explain the phage resistance observed for these two isolates (Figure 1): when Strain 1 was used as a reference, a C to A transition at position 1803 of the colicin I receptor gene caused a Tyr601->Stop transition. This receptor has been recognized as a phage receptor [7].
We further studied the course of infection by extracting DNA from the three available A. xylosoxidans-positive BAL samples (BAL#5, #6 and #9), and by quantifying DNA of the different strains by means of strain-specific qPCRs (Table 3 and Supplementary Methods) that had been developed on the basis of the obtained WGS data. qPCRs for Strain 2 and Strain 4 were only positive for the BALs from which these isolates had been cultured, respectively, BAL#5 and BAL#9. qPCR for Strain 1 was only positive for BAL#9, but not for BAL#5 from which isolate 3R had been cultured. qPCR for Strain 3 was positive for all three BALs, although no isolate belonging to Strain 3 was cultured from BAL#5.
3. Discussion and Conclusions
We report the first case of decolonization of pandrug-resistant Achromobacter xylosoxidans after a long-term follow-up in a lung-transplanted patient receiving phage therapy. The first actual demonstration and usage of bacteriophages came almost simultaneously from two microbiologists in 1915 (Frederick Twort) and 1917 (Félix d’Hérelle) [8]. After extensive clinical use during the first half of the 20th century, their use has been progressively reduced, mainly due to the discovery, rapid spread, and ease of use of antibiotics for the treatment of infectious diseases [9]. However, bacteriophages gained a new surge of attention, due to the emergence and spread of pandrug-resistant bacteria [8]. Despite decades of clinical experience with bacteriophages in Eastern Europe, very few data are available regarding their clinical efficacy; besides, case-series and few randomized controlled trials (RCT) [10,11,12]. For instance, a RCT assessed the clinical outcome of patients receiving local application of a phage cocktail for the treatment of burn wound infection. This RCT is frequently cited to have shown no clinical benefits, as compared to standard of care. However, the phage titer that was applied (100 pfu/mL) [10], was so extremely low that it precludes to draw any conclusion from this study regarding the usefulness of phage therapy. The limited number of randomized clinical trials has been recently reviewed [13]. Phage therapy has also been used locally, e.g., for the treatment of bone and joint infections [14,15] or intravenously for the treatment of bloodstream infections [16,17]. Considering the high frequency of colonization and infection caused by antibiotic-resistant bacteria among cystic fibrosis and lung-transplanted patients, such as in our patient, the use of bacteriophages appears to be an appealing option in this population [18,19,20]. In the specific case of A. xylosoxidans, thus far a single case-report described the favorable outcome after the use of bacteriophages in a cystic fibrosis patient [21].
Our case-report highlights the many difficulties that need to be taken into account before considering the use of bacteriophages in a clinical setting. These include amongst others an important delay from clinical decision to regulatory agency authorization. Most problematic is the difficult interpretation of the clinical outcome after bacteriophage therapy, considering the long-term persisting airway colonization and the possible evolution of different A. xylosoxidans strains. The second therapeutic attempt relied on a massive lung instillation (injection of the bacteriophage solution in the patient’s lung during fibroscopy) followed by a two-week course of phage nebulization. We used a vibrating mesh nebulizer for phage delivery as this type of nebulizer has been shown to result in a lower phage titer reduction, as compared to jet nebulizers [22]. BAL#9, performed two weeks after the second round of phage therapy (8 February 2018) still grew 105 CFU/mL of A. xylosoxidans, represented by Strains 3 and 4 (according to culture) and by at least Strains 1, 3 and 4 (according to qPCR) (Table 1, Table 2 and Table 3). Sputum cultures remained positive for 18 months, but with only 103 CFU A. xylosoxidans/mL, suggesting a possible upper airway colonization, especially since no A. xylosoxidans could be isolated from BALs sampled in August 2019, and April 2020. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. To more precisely understand the discrepant outcome of our patient, another option would have been to search for active phages from the BAL samples throughout the study, but this was not performed.
Despite the observed differences of a total of 367 SNPs between the four strains of eight A. xylosoxidans isolates from the patient, their overall similarity suggests that they originate from a single strain that colonized the patient (who was colonized with A. xylosoxidans years before the start of the phage therapy). Therefore, it is possible that some variants were present already before lung transplantation and before the start of phage therapy. Although it is not possible to exclude the simultaneous presence of these different strains on the basis of our culture results, because only one or two colonies were picked from each BAL culture, analysis by means of four strain-specific qPCR assays of the three BAL samples that were available for study, indicated that Strains 2 and 4 were probably prevalent at a particular moment of the course of infection, whereas Strains 1 and 3 could be identified during the full course of the infection. Phage resistant Strain 4 may have been selected during phage therapy.
Phage training has been proposed to overcome phage resistance and increase infectivity against a given bacterial population [23]. However, training phages may take weeks, and therefore might be restricted to the treatment of chronic infections. Regarding more acute infections, the establishment of phage collections (such as the DSMZ, which provided bacteriophages for our patient) is of critical importance to provide phages active against a broad spectrum of bacterial isolates.
An interesting point is the observation of two isolates from the same strain (is1S-Str1/BAL#3 and is3R-Str1/BAL#5) that differ regarding their phage susceptibility phenotype despite the absence of genetic support (identical genome). As observed with bacteria where emerging data point out that a resistance phenotype against a given antimicrobial may not be supported by a genotypic substratum [24,25], phage resistance without any change in genotype has also been documented [26]. These genotype/phenotype discrepancies are hypothesized to be possible through epigenetic regulation mechanisms, of which post-transcriptional regulation, which may influence phage receptor expression on the cell surface or phage receptor masking (through capsule synthesis). Further studies are required to better understand the dynamics of in vivo selection of phage-resistant bacteria.
Because the patient’s medical condition improved anyhow, a few weeks after the second round of phage instillation, it is possible that phage therapy selected the phage-resistant A. xylosoxidans Strain 4, but that the mutation that caused phage resistance at the same time decreased the virulence of the strain as already described with other bacteria and phages [27,28,29]. Indeed, we observed several mutations which could explain the phage resistance of Strain 4, of which one was especially interesting, since it caused the gain of a stop codon in the colicin I receptor, which has been recognized as a phage receptor in other species [7]. Because in E. coli, the colicin I receptor plays a crucial role in iron transport across the outer membrane [7], loss of this function due to the observed mutation may have caused reduced fitness of the A. xylosoxidans mutant Strain 4. However, from a clinical point-of-view, one cannot exclude a spontaneous improvement, independently of phage therapy and despite months of fruitless antibiotic treatment, highlighting the dire need of randomized clinical trials in order to more convincingly assess the clinical efficacy of bacteriophages.
In conclusion, we describe the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. Despite initial persisting airway colonization, the final clinical and microbiological outcome was favorable. Whole genome sequencing of eight A. xylosoxidans isolates and strain-specific qPCR experiments performed on BALs sampled before and after phage therapy allowed to more precisely study the dynamics of lung colonization by different isolates, susceptible or resistant to the applied phage cocktails.
Acknowledgments
The authors would like to thank L. Lécuyer and V. Boussaud (Unité de Transplantation, HEGP), B. Sabatier, V. Savoldelli, T. Caruba and P. Prognon (Pharmacie HEGP), P. Odou, C. Nassar, C. Berneron and M. Roche (Pharmacie Lille), and E. Deberranger (Hématologie Pédiatrique Lille), for their help in the management of the patient. Microbiological analysis was performed with a funding by the Association Robert Debré pour la Recherche Médicale. The authors would also like to thank Caroline Semaille and Nathalie Morgensztejn from the Agence Nationale de Sécurité du Médicament (ANSM) for their regulatory support.
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Supplementary Materials
The following are available online at https://www.mdpi.com/1999-4915/13/1/60/s1, Figure S1: Antibiotic susceptibility testing (AST) of a pandrug-resistant Achromobacter xylosoxidans isolated during a bronchoalveolar lavage of a 12-year-old boy after double lung transplantation, Table S1: Variant calling for the eight Achromobacter xylosoxidans whole genome sequences, see excel file attached, named: “Supplementary Table S1. Variant calling.xls”.
Click here for additional data file.
Author Contributions
D.L. (David Lebeaux) and M.V. conceptualized the study, validated the data, carried out formal analysis, prepared the initial draft, took care of project administration and supervised the study. Data were visualized by H.D. and Y.G. Software analysis was carried out by H.D., S.V., Y.G. D.L. (David Lebeaux), M.M., R.G., I.P., F.C., N.K., J.W., C.R., E.C., D.L. (Damien Lanoy), L.V.S., H.D., J.-P.P., N.D., S.V., Y.G., F.V.N., and M.V. contributed to basic methodology. Data curation was done by D.L. (David Lebeaux), M.M., C.T., S.V., Y.G., and M.V. Funding was acquired by D.L. (David Lebeaux), J.-L.M., F.V.N., and M.V. All authors took part in the investigation and in final reviewing and editing of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study did not require ethical approval.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The sequencing reads and genome sequences of all isolates have been submitted to the European Nucleotide Archive (ENA) and are available under project number PRJEB39103 (Table 2). (https://www.ebi.ac.uk/ena/browser/view/PRJEB39103).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Phylogenetic tree built with Whole genome sequences of eight Achromobacter xylosoxidans strains isolated in a 12-year-old boy after double lung transplantation. The distance between samples reflects the number of different Single Nucleotide Polymorphisms (SNPs). Each A. xylosoxidans is named as follows: isolate number (is1 to is8) S (or R to depict susceptibility or resistance to phage cocktail)-Strain number/Number of BAL where it has been identified.
viruses-13-00060-t001_Table 1Table 1 Results of bronchoalveolar lavages (BALs) and sputum analysis from May 2017, to April 2020, in 12-year-old lung transplanted patient who received two rounds of phage therapy for pandrug-resistant Achromobacter xylosoxidans colonization and infection.
Date 19 May 2017 23 May 2017 6 June 2017 12 June 2017 25 July 2017 5 September 2017 8 September 2017 15 September 2017 12 October 2017 27 October 2017 23 January 2018 8 February 2018 5 March 2018 18 May 2018 19 February 2019 19 June 2019 27 August 2019 30 April 2020
Phage therapy
ROUND 1
ROUND 2
Tigecycline
from 29 June to 31 July
Imipenem
From 31 July 2017, to 16 February 2018
Number of days, relative to the first round of phage therapy −112 −108 −94 −88 −45 −3
+7 +37 +49 +137 +153 +178 +252 +529 +649 +718 +963
BAL
BAL Number * #1
#2 #3 #4
#5
#6
#7 #8
#9
#10
#11 #12
Leukocytes (/mm3) >1000
800 >1000 500
>1000 60 >1000 810 >1000
NA
NA NA
PMN cells (%) 90
88 90 91
43 30 80 69 82
NA
NA NA
Quantification of A. x culture (CFU/mL)
104
103
104
103
104
103
104
106
105
104
0
0
Other bacteria (CFU/mL) None
None None None
None None None None None
None
104
S. a 106
S. a
Sputum
Leucocytes (/field)
>25 >25
>25
>25
NA NA
NA
Quantification of A. x culture (CFU/mL)
105
105
105
106
103
103
103
Other bacteria (CFU/mL)
None None
None
None
108
M. c None
106
S. a
A. x: Achromobacter xylosoxidans; M. c: Moraxella catarrhalis; NA: non available; PMN: Polymorphonuclear; RBC: red blood cells; S. a: Staphylococcus aureus. *: BAL number in bold indicates BALs for which qPCR had been carried out.
viruses-13-00060-t002_Table 2Table 2 Eight Achromobacter xylosoxidans isolates for which whole genome sequencing was carried out. These were isolated from bronchoalveolar lavages in a 12-year-old boy after double lung transplantation. The patient received a first round of phage administration on 8 September 2017. A second round of phage treatment was performed on 23 January 2018.
Complete Name Isolate Strain Source of Sampling Date of Sampling Whole Genome Sequence *
is1S-Str1/BAL#3 is1S Str1 BAL#3 25 July 2017 ERS5044236-UGAX1
is2S-Str2/BAL#5 is2S Str2 BAL#5 15 September 2017 ERS5044237-UGAX2
is3R-Str1/BAL#5 is3R Str1 BAL#5 15 September 2017 ERS5044238-UGAX3
is5S-Str3/BAL#6 is5S Str3 BAL#6 12 October 2017 ERS5044239-UGAX5
is6S-Str3/BAL#6 is6S Str3 BAL#6 12 October 2017 ERS5044240-UGAX6
is7R-Str4/BAL#9 is7R Str4 BAL#9 8 February 2018 ERS5044241-UGAX7
is8R-Str4/BAL#9 is8R Str4 BAL#9 8 February 2018 ERS5044242-UGAX8
is9S-Str3/BAL#9 is9S Str3 BAL#9 8 February 2018 ERS5044243-UGAX9
* Submitted at ENA, 1 September 2020. Study ID: PRJEB39103. BAL: Bronchoalveolar lavage, S: Phage susceptible, R: phage resistant.
viruses-13-00060-t003_Table 3Table 3 Results of bacterial culture (grey-shading) and qPCR of three broncho-alveolar lavages for four different Achromobacter xylosoxidans strains isolated in a 12-year-old boy after double lung transplantation.
Bronchoalveolar Lavage BAL#5 BAL#6 BAL#9
15 September 2017 12 October 2017 8 February 2018
qPCR for Strain Isolates
Str1 is1S, is3R N NS P (34.7)
Str2 is2S P (36.6) N N
Str3 is5S, is6S, is9S P (32.7) P (28.9) P (27.7)
Str4 is7R, is8R NS NS P (35.2)
Grey-shaded box = isolate cultured from this BAL; N: negative (Cq-value > 40); NS: Nonspecific amplification (melting peak different from that of specific amplification); P: positive qPCR (Cq-value). | MYCOPHENOLATE MOFETIL, POSACONAZOLE, PREDNISOLONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33466377 | 19,957,163 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Moraxella infection'. | A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient.
Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient's respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.
1. Case Presentation
We report the case of a 12-year-old boy (35.5 kg), who received double lung transplantation in 25 March 2017, (at the age of 12) because of cystic fibrosis. Before transplantation, he was colonized with Aspergillus fumigatus, Achromobacter xylosoxidans (first colonization identified in 2013), and Pseudomonas aeruginosa. After transplantation, he experienced acute kidney injury requiring temporary haemodialysis, pulmonary embolism, and persisting airway colonization with A. fumigatus. He was discharged on 29 April 2017, with satisfactory respiratory status; he initially required no home oxygen therapy. His immunosuppressive regimen included prednisolone (25 mg/day), tacrolimus (1.5 mg bis in die (b.i.d.) with a target trough concentration of 6–8 ng/mL), mycophenolate mofetil (1 g b.i.d.) and his antimicrobial prophylaxis was cotrimoxazole (400/80 mg, three times a week), posaconazole (150 mg, oral suspension, ter in die (t.i.d.)), valacyclovir (500 mg b.i.d.), and intravenous immunoglobulins (15 g each three weeks).
Between May and June 2017, he experienced progressive shortness of breath, cough and increased sputum production; he subsequently required the addition of 1–1.5 L/min oxygen therapy. Because of a stenosis of the surgical anastomosis of the main left bronchus, a dilatation during rigid bronchoscopy was performed on 19 May and a Montgomery stent was inserted on 2 June. Later on, a stenosis of the surgical anastomosis on the right bronchus intermedius required a dilatation during rigid bronchoscopy followed by the insertion of an Oki stent on 29 June.
Several bronchoalveolar lavages (BAL), performed between May and June 2017, revealed inflammation (between 800 and >1000 leukocytes/mm3 with 88–90% of polymorphonuclear cells) and repeatedly grew pandrug-resistant A. xylosoxidans (Table 1 and Supplementary Figure S1) [1]. Lung biopsy performed on 19 June was consistent with lung infection: diffuse acute bronchiolitis with extension to peri-bronchiolar alveoli. Microbiological samples obtained from lung biopsies were negative (bacterial, mycological, and mycobacteriological cultures). The first antibiotic treatment consisted of intravenous tigecycline 50 mg b.i.d. from 29 June to 31 July. As BAL remained positive for A. xylosoxidans and the patient still required oxygen therapy; antibiotic treatment was subsequently switched to imipenem (1200 mg, t.i.d., ~100 mg/Kg/d) on 31 July 2017. Subsequent respiratory samples still grew A. xylosoxidans and the respiratory status did not improve (requiring oxygen at home, 1 L/min). Furthermore, despite antibiotic treatment and correct drainage of the right superior lobe, lung consolidation and micronodules remained.
Considering the failure of antibiotic treatment, phage therapy was proposed to the patient and his family, after multidisciplinary discussion. A first cocktail (APC 1.1) containing three lytic phages (JWDelta, JWT and 2-1) active against A. xylosoxidans isolate is1S (designated such as later), selected from the DSMZ collection (Braunschweig, Germany) [2,3], was prepared at the Laboratory for Bacteriology Research (Ghent University, Belgium) and the Laboratory for Molecular and Cellular Technology (Queen Astrid Military Hospital, Brussels, Belgium) using the above-mentioned bacterial isolate, as previously described [4]. The production was completed on 23 August with a final phage titer of 4 × 1010 plaque forming units (pfu)/mL defined by double-agar overlay method [4], an endotoxin level of 4000 EU/mL (ToxinSensor Chromogenic LAL Endotoxin Assay Kit, GenScript, Piscataway Township, NJ, USA) and a pH of 7.3 (in sterile PBS). Regulatory permission for phage importation was obtained on 1 September 2017, from the Agence Nationale de Sécurité du Médicament (ANSM). A first round of phage administration was performed, consisting of 3 nebulizations/day of 5 mL of the filter-sterilized (Sartorius 0.2 µm) phage solution, tenfold diluted in sterile saline on 8 and 9 September, using a vibrating mesh nebulizer (eFLOW rapid, PARI, PARI GmbH, Germany) with a mouth piece. Immediate tolerance was perfect, but no clinical improvement was noted and culture of subsequent respiratory samples remained positive for A. xylosoxidans (104 CFU/mL in the BAL of 15 September).
A second cocktail (APC 2.1) was produced, in which phage JWalpha was added to the three lytic phages of cocktail APC 1.1, to improve the therapeutic efficacy. The production was completed on 22 December with a final phage titer of 5 × 109 pfu/mL, an endotoxin level of 1760 EU/mL and a pH of 6.95 (in sterile PBS). Regulatory permission was obtained for phage importation on 16 January 2018 (ANSM). On 23 January, during therapeutic bronchoscopy under general anesthesia, 30 mL of APC2.1, tenfold diluted (in sterile saline) and filter-sterilized, was instilled in each pulmonary lobe through the fibroscope. Immediate tolerance was perfect and the patient was discharged on 24 January with continued phage nebulization at home: three times a day 5 mL of preparation A using a vibrating mesh nebulizer (eFLOW rapid, PARI) with a mouth piece for 14 days until 6 February. Clinical tolerance was perfect again, but the initial clinical status remained unchanged. BAL performed on 8 February 2018, two days after stopping the phage treatment, still grew 105 cfu/mL of A. xylosoxidans. Subsequently, the patient’s respiratory condition slowly improved and oxygen therapy was stopped on 15 February 2018. No clinical worsening was observed after imipenem interruption on 16 February 2018. Sputum culture remained positive for A. xylosoxidans but with a low bacterial density (103 CFU/mL in March and May 2018, and June 2019) and no A. xylosoxidans could be isolated from BALs#10 and #11, sampled on August 2019, and April 2020, respectively (Table 1). The last pulmonary function tests, performed on 17 October 2019, showed best results since lung transplantation, with an FEV1 of 79% and a forced vital capacity of 85%.
2. Microbiological Analysis of Eight A. xylosoxidans Isolates
As we observed discrepant outcome in our patient (clinical improvement on the one hand but persisting low-grade airway colonization on the other hand), we decided to study the eight available A. xylosoxidans isolates (is1 to is9) from the patient’s colonization obtained by random picking from the culture plates from 4 distinct BALs (Table 2). These eight isolates, taken before, during and after the phage therapy period (Table 2), could not be differentiated from each other by means of MALDI-TOF [5] or McRAPD typing [6] and all belonged to the epidemic clone, already described previously among Belgian CF patients [5]. Whole genome sequencing (WGS) and de novo genome assembly for these eight isolates was carried out (Supplementary Methods and Table S1). The sequencing reads and genome sequences of all isolates have been submitted to the European Nucleotide Archive (ENA) and are available under project number PRJEB39103 (Table 2). (https://www.ebi.ac.uk/ena/browser/view/PRJEB39103).
Total genome length for all eight isolates was 6.44–6.50 Mbp, with a GC content of 67.5%. All eight isolates showed most similarity with reference genome GCF_008432465 (AX1), which corresponds to the type strain of A. xylosoxidans subsp. xylosoxidans (ATCC 27061T, CCUG 12689T, DSMZ 10346T, LMG 1863T, and NCTC 10807T), i.e., between 88.38 and 89.60% on the basis of mapped sequence reads, and between 98.71% and 98.76% on the basis of average nucleotide identity (ANI). Indeed, the overall similarity between the genome sequences of the eight isolates was high, i.e., 99.60%, as assessed by digital DNA hybridization, and more than 99.97% according to ANI-analysis. This was confirmed by variant calling where we observed that the isolates differed from each other only for a total of 367 SNPs, whereas a total of 59,452 SNPs were observed between the isolates and the best matching reference genome (AX1) (Figure 1). The susceptibility phenotype of each of the eight isolates was assessed by spot-test against the phage cocktail APC 2.1 and expressed as “S” when susceptible or “R” when resistant (e.g., “is2S” means that isolate number 2 was susceptible to the phage cocktail) (Table 2 and Supplementary Methods). Among these eight isolates, analysis based on variant calling furthermore revealed four closely related but clearly delineated strains, i.e., clones that differ genetically from other clones, with different phage susceptibility phenotype (Table 2 and Figure 1): Strain 1 (Str1), contained isolates 1 and 3 (is1S and is3R), found in BAL#3 (is1S-Str1/BAL#3) and BAL#5 (is3R-Str1/BAL#5), respectively. Strain 2 (Str2) contained isolate 2 (is2S) from BAL#5 (is2S-Str2/BAL#5). Strain 3 (Str3) contained isolates 5, 6, and 9 (is5S, is6S and is9S), which were found in BAL#6 (is5S-Str3/BAL#6, is6S-Str3/BAL#6) and BAL#9 (is9S-Str3/BAL#9). Strain 4 contained isolates 7 and 8 (is7R and is8R), found in BAL#9 (is7R-Str4/BAL#9 and is8R-Str4/BAL#9) (Table 2).
Isolate is1S-Str1/BAL#3 was obtained on 25 July 2017, i.e., 45 days before the first phage therapy session (8 September 2017) and was 100% identical to is3R-Str1/BAL#5 isolated seven days (15 September 2017) after the first phage therapy session (Figure 1). Since both isolates is1S-Str1/BAL#3 and is3R-Str1/BAL#5 are 100% identical, this means that the phage resistance mechanism of isolate is3R-Str1/BAL#5 is not genetically supported (see discussion). Isolates is5S-Str3/BAL#6 and is6S-Str3/BAL#6, both phage susceptible, were obtained one month later (12 October 2017) and belonged to still another strain (Strain 3). Finally, on 8 February 2018, i.e., 16 days after the second phage therapy session (23 January 2018), an additional three isolates were obtained from BAL#9. Of these, isolate is9S-Str3/BAL#9 belonged to the same Strain 3 as isolates is5S-Str3/BAL#6 and is6S-Str3/BAL#6 and was phage susceptible as well, but isolates 7R and 8R belonged to still another strain (Strain 4) and were both resistant to the phage cocktail. Interestingly, the phage resistant Strain 4 isolates (is7R-Str4/BAL#9 and is8R-Str4/BAL#9) contained mutations compared to the other six isolates that could explain the phage resistance observed for these two isolates (Figure 1): when Strain 1 was used as a reference, a C to A transition at position 1803 of the colicin I receptor gene caused a Tyr601->Stop transition. This receptor has been recognized as a phage receptor [7].
We further studied the course of infection by extracting DNA from the three available A. xylosoxidans-positive BAL samples (BAL#5, #6 and #9), and by quantifying DNA of the different strains by means of strain-specific qPCRs (Table 3 and Supplementary Methods) that had been developed on the basis of the obtained WGS data. qPCRs for Strain 2 and Strain 4 were only positive for the BALs from which these isolates had been cultured, respectively, BAL#5 and BAL#9. qPCR for Strain 1 was only positive for BAL#9, but not for BAL#5 from which isolate 3R had been cultured. qPCR for Strain 3 was positive for all three BALs, although no isolate belonging to Strain 3 was cultured from BAL#5.
3. Discussion and Conclusions
We report the first case of decolonization of pandrug-resistant Achromobacter xylosoxidans after a long-term follow-up in a lung-transplanted patient receiving phage therapy. The first actual demonstration and usage of bacteriophages came almost simultaneously from two microbiologists in 1915 (Frederick Twort) and 1917 (Félix d’Hérelle) [8]. After extensive clinical use during the first half of the 20th century, their use has been progressively reduced, mainly due to the discovery, rapid spread, and ease of use of antibiotics for the treatment of infectious diseases [9]. However, bacteriophages gained a new surge of attention, due to the emergence and spread of pandrug-resistant bacteria [8]. Despite decades of clinical experience with bacteriophages in Eastern Europe, very few data are available regarding their clinical efficacy; besides, case-series and few randomized controlled trials (RCT) [10,11,12]. For instance, a RCT assessed the clinical outcome of patients receiving local application of a phage cocktail for the treatment of burn wound infection. This RCT is frequently cited to have shown no clinical benefits, as compared to standard of care. However, the phage titer that was applied (100 pfu/mL) [10], was so extremely low that it precludes to draw any conclusion from this study regarding the usefulness of phage therapy. The limited number of randomized clinical trials has been recently reviewed [13]. Phage therapy has also been used locally, e.g., for the treatment of bone and joint infections [14,15] or intravenously for the treatment of bloodstream infections [16,17]. Considering the high frequency of colonization and infection caused by antibiotic-resistant bacteria among cystic fibrosis and lung-transplanted patients, such as in our patient, the use of bacteriophages appears to be an appealing option in this population [18,19,20]. In the specific case of A. xylosoxidans, thus far a single case-report described the favorable outcome after the use of bacteriophages in a cystic fibrosis patient [21].
Our case-report highlights the many difficulties that need to be taken into account before considering the use of bacteriophages in a clinical setting. These include amongst others an important delay from clinical decision to regulatory agency authorization. Most problematic is the difficult interpretation of the clinical outcome after bacteriophage therapy, considering the long-term persisting airway colonization and the possible evolution of different A. xylosoxidans strains. The second therapeutic attempt relied on a massive lung instillation (injection of the bacteriophage solution in the patient’s lung during fibroscopy) followed by a two-week course of phage nebulization. We used a vibrating mesh nebulizer for phage delivery as this type of nebulizer has been shown to result in a lower phage titer reduction, as compared to jet nebulizers [22]. BAL#9, performed two weeks after the second round of phage therapy (8 February 2018) still grew 105 CFU/mL of A. xylosoxidans, represented by Strains 3 and 4 (according to culture) and by at least Strains 1, 3 and 4 (according to qPCR) (Table 1, Table 2 and Table 3). Sputum cultures remained positive for 18 months, but with only 103 CFU A. xylosoxidans/mL, suggesting a possible upper airway colonization, especially since no A. xylosoxidans could be isolated from BALs sampled in August 2019, and April 2020. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. To more precisely understand the discrepant outcome of our patient, another option would have been to search for active phages from the BAL samples throughout the study, but this was not performed.
Despite the observed differences of a total of 367 SNPs between the four strains of eight A. xylosoxidans isolates from the patient, their overall similarity suggests that they originate from a single strain that colonized the patient (who was colonized with A. xylosoxidans years before the start of the phage therapy). Therefore, it is possible that some variants were present already before lung transplantation and before the start of phage therapy. Although it is not possible to exclude the simultaneous presence of these different strains on the basis of our culture results, because only one or two colonies were picked from each BAL culture, analysis by means of four strain-specific qPCR assays of the three BAL samples that were available for study, indicated that Strains 2 and 4 were probably prevalent at a particular moment of the course of infection, whereas Strains 1 and 3 could be identified during the full course of the infection. Phage resistant Strain 4 may have been selected during phage therapy.
Phage training has been proposed to overcome phage resistance and increase infectivity against a given bacterial population [23]. However, training phages may take weeks, and therefore might be restricted to the treatment of chronic infections. Regarding more acute infections, the establishment of phage collections (such as the DSMZ, which provided bacteriophages for our patient) is of critical importance to provide phages active against a broad spectrum of bacterial isolates.
An interesting point is the observation of two isolates from the same strain (is1S-Str1/BAL#3 and is3R-Str1/BAL#5) that differ regarding their phage susceptibility phenotype despite the absence of genetic support (identical genome). As observed with bacteria where emerging data point out that a resistance phenotype against a given antimicrobial may not be supported by a genotypic substratum [24,25], phage resistance without any change in genotype has also been documented [26]. These genotype/phenotype discrepancies are hypothesized to be possible through epigenetic regulation mechanisms, of which post-transcriptional regulation, which may influence phage receptor expression on the cell surface or phage receptor masking (through capsule synthesis). Further studies are required to better understand the dynamics of in vivo selection of phage-resistant bacteria.
Because the patient’s medical condition improved anyhow, a few weeks after the second round of phage instillation, it is possible that phage therapy selected the phage-resistant A. xylosoxidans Strain 4, but that the mutation that caused phage resistance at the same time decreased the virulence of the strain as already described with other bacteria and phages [27,28,29]. Indeed, we observed several mutations which could explain the phage resistance of Strain 4, of which one was especially interesting, since it caused the gain of a stop codon in the colicin I receptor, which has been recognized as a phage receptor in other species [7]. Because in E. coli, the colicin I receptor plays a crucial role in iron transport across the outer membrane [7], loss of this function due to the observed mutation may have caused reduced fitness of the A. xylosoxidans mutant Strain 4. However, from a clinical point-of-view, one cannot exclude a spontaneous improvement, independently of phage therapy and despite months of fruitless antibiotic treatment, highlighting the dire need of randomized clinical trials in order to more convincingly assess the clinical efficacy of bacteriophages.
In conclusion, we describe the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. Despite initial persisting airway colonization, the final clinical and microbiological outcome was favorable. Whole genome sequencing of eight A. xylosoxidans isolates and strain-specific qPCR experiments performed on BALs sampled before and after phage therapy allowed to more precisely study the dynamics of lung colonization by different isolates, susceptible or resistant to the applied phage cocktails.
Acknowledgments
The authors would like to thank L. Lécuyer and V. Boussaud (Unité de Transplantation, HEGP), B. Sabatier, V. Savoldelli, T. Caruba and P. Prognon (Pharmacie HEGP), P. Odou, C. Nassar, C. Berneron and M. Roche (Pharmacie Lille), and E. Deberranger (Hématologie Pédiatrique Lille), for their help in the management of the patient. Microbiological analysis was performed with a funding by the Association Robert Debré pour la Recherche Médicale. The authors would also like to thank Caroline Semaille and Nathalie Morgensztejn from the Agence Nationale de Sécurité du Médicament (ANSM) for their regulatory support.
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Supplementary Materials
The following are available online at https://www.mdpi.com/1999-4915/13/1/60/s1, Figure S1: Antibiotic susceptibility testing (AST) of a pandrug-resistant Achromobacter xylosoxidans isolated during a bronchoalveolar lavage of a 12-year-old boy after double lung transplantation, Table S1: Variant calling for the eight Achromobacter xylosoxidans whole genome sequences, see excel file attached, named: “Supplementary Table S1. Variant calling.xls”.
Click here for additional data file.
Author Contributions
D.L. (David Lebeaux) and M.V. conceptualized the study, validated the data, carried out formal analysis, prepared the initial draft, took care of project administration and supervised the study. Data were visualized by H.D. and Y.G. Software analysis was carried out by H.D., S.V., Y.G. D.L. (David Lebeaux), M.M., R.G., I.P., F.C., N.K., J.W., C.R., E.C., D.L. (Damien Lanoy), L.V.S., H.D., J.-P.P., N.D., S.V., Y.G., F.V.N., and M.V. contributed to basic methodology. Data curation was done by D.L. (David Lebeaux), M.M., C.T., S.V., Y.G., and M.V. Funding was acquired by D.L. (David Lebeaux), J.-L.M., F.V.N., and M.V. All authors took part in the investigation and in final reviewing and editing of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study did not require ethical approval.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The sequencing reads and genome sequences of all isolates have been submitted to the European Nucleotide Archive (ENA) and are available under project number PRJEB39103 (Table 2). (https://www.ebi.ac.uk/ena/browser/view/PRJEB39103).
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Phylogenetic tree built with Whole genome sequences of eight Achromobacter xylosoxidans strains isolated in a 12-year-old boy after double lung transplantation. The distance between samples reflects the number of different Single Nucleotide Polymorphisms (SNPs). Each A. xylosoxidans is named as follows: isolate number (is1 to is8) S (or R to depict susceptibility or resistance to phage cocktail)-Strain number/Number of BAL where it has been identified.
viruses-13-00060-t001_Table 1Table 1 Results of bronchoalveolar lavages (BALs) and sputum analysis from May 2017, to April 2020, in 12-year-old lung transplanted patient who received two rounds of phage therapy for pandrug-resistant Achromobacter xylosoxidans colonization and infection.
Date 19 May 2017 23 May 2017 6 June 2017 12 June 2017 25 July 2017 5 September 2017 8 September 2017 15 September 2017 12 October 2017 27 October 2017 23 January 2018 8 February 2018 5 March 2018 18 May 2018 19 February 2019 19 June 2019 27 August 2019 30 April 2020
Phage therapy
ROUND 1
ROUND 2
Tigecycline
from 29 June to 31 July
Imipenem
From 31 July 2017, to 16 February 2018
Number of days, relative to the first round of phage therapy −112 −108 −94 −88 −45 −3
+7 +37 +49 +137 +153 +178 +252 +529 +649 +718 +963
BAL
BAL Number * #1
#2 #3 #4
#5
#6
#7 #8
#9
#10
#11 #12
Leukocytes (/mm3) >1000
800 >1000 500
>1000 60 >1000 810 >1000
NA
NA NA
PMN cells (%) 90
88 90 91
43 30 80 69 82
NA
NA NA
Quantification of A. x culture (CFU/mL)
104
103
104
103
104
103
104
106
105
104
0
0
Other bacteria (CFU/mL) None
None None None
None None None None None
None
104
S. a 106
S. a
Sputum
Leucocytes (/field)
>25 >25
>25
>25
NA NA
NA
Quantification of A. x culture (CFU/mL)
105
105
105
106
103
103
103
Other bacteria (CFU/mL)
None None
None
None
108
M. c None
106
S. a
A. x: Achromobacter xylosoxidans; M. c: Moraxella catarrhalis; NA: non available; PMN: Polymorphonuclear; RBC: red blood cells; S. a: Staphylococcus aureus. *: BAL number in bold indicates BALs for which qPCR had been carried out.
viruses-13-00060-t002_Table 2Table 2 Eight Achromobacter xylosoxidans isolates for which whole genome sequencing was carried out. These were isolated from bronchoalveolar lavages in a 12-year-old boy after double lung transplantation. The patient received a first round of phage administration on 8 September 2017. A second round of phage treatment was performed on 23 January 2018.
Complete Name Isolate Strain Source of Sampling Date of Sampling Whole Genome Sequence *
is1S-Str1/BAL#3 is1S Str1 BAL#3 25 July 2017 ERS5044236-UGAX1
is2S-Str2/BAL#5 is2S Str2 BAL#5 15 September 2017 ERS5044237-UGAX2
is3R-Str1/BAL#5 is3R Str1 BAL#5 15 September 2017 ERS5044238-UGAX3
is5S-Str3/BAL#6 is5S Str3 BAL#6 12 October 2017 ERS5044239-UGAX5
is6S-Str3/BAL#6 is6S Str3 BAL#6 12 October 2017 ERS5044240-UGAX6
is7R-Str4/BAL#9 is7R Str4 BAL#9 8 February 2018 ERS5044241-UGAX7
is8R-Str4/BAL#9 is8R Str4 BAL#9 8 February 2018 ERS5044242-UGAX8
is9S-Str3/BAL#9 is9S Str3 BAL#9 8 February 2018 ERS5044243-UGAX9
* Submitted at ENA, 1 September 2020. Study ID: PRJEB39103. BAL: Bronchoalveolar lavage, S: Phage susceptible, R: phage resistant.
viruses-13-00060-t003_Table 3Table 3 Results of bacterial culture (grey-shading) and qPCR of three broncho-alveolar lavages for four different Achromobacter xylosoxidans strains isolated in a 12-year-old boy after double lung transplantation.
Bronchoalveolar Lavage BAL#5 BAL#6 BAL#9
15 September 2017 12 October 2017 8 February 2018
qPCR for Strain Isolates
Str1 is1S, is3R N NS P (34.7)
Str2 is2S P (36.6) N N
Str3 is5S, is6S, is9S P (32.7) P (28.9) P (27.7)
Str4 is7R, is8R NS NS P (35.2)
Grey-shaded box = isolate cultured from this BAL; N: negative (Cq-value > 40); NS: Nonspecific amplification (melting peak different from that of specific amplification); P: positive qPCR (Cq-value). | MYCOPHENOLATE MOFETIL, POSACONAZOLE, PREDNISOLONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS, VALACYCLOVIR HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33466377 | 19,957,163 | 2021-01-05 |
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