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Acute respiratory distress syndrome following alemtuzumab therapy for relapsing multiple sclerosis
Multiple Sclerosis and Related Disorders 14 (2017) 1–3
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Case report
MARK
Acute respiratory distress syndrome following alemtuzumab therapy for relapsing multiple sclerosis Keh Yann, Jackson Fran, Sharaf Nazar, Mihalova Tatiana, Talbot Paul, Rog David, Pace Adrian
⁎
Greater Manchester Multiple Sclerosis Group, Salford Royal NHS Foundation Trust, UK
A R T I C L E I N F O
A B S T R A C T
Keywords: Alemtuzumab Multiple sclerosis Pneumocystis jirovecii Cytomegalovirus ARDS
We present the case of a 54 year old woman with known relapsing-remitting multiple sclerosis who presented with acute respiratory deterioration five weeks after a first course of alemtuzumab. Imaging showed bilateral ground glass changes and extensive investigations confirmed chest infection with dual pathogens - Pneumocystis jirovecii and Cytomegalovirus. She responded to standard anti-PJP and CMV therapy and was discharged on oral prophylaxis. Opportunistic infections in the weeks immediately following alemtuzumab therapy remain an uncommon complication but one that requires clinical vigilance, careful monitoring and appropriate prophylactic therapy.
1. Case report A 54 year old woman received a 5-day course of intravenous alemtuzumab in May 2015 for active relapsing-remitting multiple sclerosis (RRMS). She was diagnosed with RRMS in 2004 and started immediately on Betaferon. In October 2011 she was switched to Copaxone due to ongoing relapses but changed again to Avonex in August 2012 after experiencing a delayed allergic-type reaction. In March 2015 she suffered a disabling relapse with left hemiparesis, spasticity and deteriorating mobility. Her last relapses on treatment had been in February 2014 and October 2012. In view of ongoing disease activity, alternative treatment options were discussed and she chose alemtuzumab. Past medical history included laparoscopic right hemicolectomy with ileocolonic anastomosis in 2013 for terminal ileal neuroendocrine tumour (grade 3 carcinoid), asthma, hysterectomy, and cholecystectomy complicated by left popliteal DVT and pulmonary embolus. Her family history was unremarkable. She did not smoke and had not recently travelled abroad. Following discharge she developed malaise, fatigue, nausea, anorexia and sweating. Monitoring blood tests 4 weeks post-treatment showed lymphopaenia (0.6×103/mm3), microcytosis (79.3 fL) and raised ALP (133U/L). Five weeks post-treatment she presented to our emergency department with dyspnoea, cough and haemoptysis. On examination she was pyrexial (38.4 °C), tachypnoeic (20 respirations/ min), hypotensive (BP 98/60 mmHg) and tachycardic (90 bpm). Oxygen saturation dropped to 72% on minimal exertion. There was ⁎
no meningism, lymphadenopathy, rash, jaundice or cyanosis. Chest auscultation revealed bibasal inspiratory crepitations. Neurological and abdominal examinations were unremarkable. Renal, liver and thyroid function tests, glucose, clotting screen, D-dimer and calcium were normal. Arterial blood gases showed Type 1 respiratory failure (pCO2 4.1 kPa; pO2 8.2 kPa) on air, full blood count confirmed lymphopaenia (0.6×109/L) and CRP was raised (38 mg/L; N≤5 mg/L). Chest X-ray showed bibasilar reticulonodular shadowing. She was admitted and treated empirically with intravenous acyclovir, co-amoxiclav and clarithromycin for presumed pneumonia. The next day later she remained febrile and became increasingly dyspnoeic. Her antibiotics were changed to intravenous benzylpenicillin, doxycycline and clindamycin, and she was started on Primaquine to cover for Pneumocystis jiroveci pneumonia (PJP). Computed Tomography pulmonary angiography(CTPA) excluded embolism but showed bilateral patchy consolidation and ground glass opacities without lymphadenopathy or pleural effusion (Fig. 1). Due to worsening oxygenation despite non-invasive respiratory support, she was transferred to intensive care for intubation and ventilation on the fourth day of admission. Bronchoalveolar lavage (BAL) washings were sent for microbiological and virology studies. Her level of arterial hypoxaemia (with a calculated pO2/FiO2 ratio of 292 mmHg) and the presence of bilateral radiographic changes fulfilled Berlin criteria for acute respiratory distress syndrome (ARDS) (The ARDS Definition Task Force Acute respiratory distress syndrome: the Berlin definition, 2012) At this point an inflammatory pneumonitis/ alveolitis was suspected as the underlying cause and she was given intravenous methylprednisolone (1 g daily for 3 days), followed by a
Correspondence to: Department of Neurology, Level 3, Humphrey Booth Building, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, United Kingdom. E-mail address: [email protected] (P. Adrian).
http://dx.doi.org/10.1016/j.msard.2017.03.001 Received 20 February 2017; Accepted 5 March 2017 2211-0348/ Crown Copyright © 2017 Published by Elsevier B.V. All rights reserved.
Multiple Sclerosis and Related Disorders 14 (2017) 1–3
K. Yann et al.
Fig. 1. CTPA imaging showing patchy bilateral ground glass changes.
Another risk is the potential exposure of patients receiving alemtuzumab to opportunistic infection in initial months following treatment, when B and T lymphocyte populations are profoundly depleted. To some extent, concern has been assuaged following clinical trial safety outcomes, where infections were more common following alemtuzumab compared to interferon beta 1a but predominantly mild-moderate in severity (Coles, 2013). Reasons proposed for this include preservation of haematopoietic stem cells (which do not express CD52) in bone marrow and thymus and lesser reduction in central memory, effector memory and regulatory T-cell numbers, suggesting innate memory responses remain intact following treatment. A further possibility is the drug's administration as a single short course, which allows B- and Tlymphocyte populations to reconstitute almost completely within months. Despite these considerations, patients with MS are still vulnerable to opportunistic infections from external agents or reactivation of dormant viruses in the first weeks following treatment with alemtuzumab (Willis et al., 2016). In clinical trials an increased risk of herpetic infections was noted (Willis et al., 2016; Tuohy et al., 2015), and acyclovir is now given during and for 28 days following treatment. While 200 mg BD of acyclovir was given in the CARE-MS trials, the authors’ practice is to prescribe 400 mg BD as local microbiological advice suggests that this conveys better prophylaxis. To the authors’ knowledge, this is the first case of ARDS secondary to alemtuzumab in the context of MS therapy described in the literature. It highlights the need for vigilance by both patients and physicians to systemic symptoms early after therapy, even when nonspecific, as these may indicate emergent opportunistic infections. This case is unusual in that the patient's respiratory deterioration was due to dual infection with PJP and CMV. As alemtuzumab use in RRMS becomes increasingly common, it remains to be seen whether further associations with these infections will emerge, and if this will warrant a change in recommendations for prophylaxis in the future.
steroid taper. Urine Legionella and Pneumococcal antigens, bacterial and TB cultures and HIV tests were negative. Virology and PCR studies were negative for influenza A and B, RSV, mycoplasma, metapneumovirus, adenovirus, rhinovirus and parainfluenza virus types 1–3, but confirmed the presence of Pneumocystis jirovecii. Blood PCR was also strongly positive for CMV (13008 IU/ml) and the BAL sample yielded 1.4 million copies of CMV/ml, consistent with active infection. She received a 2 week course of IV ganciclovir. By the second week of admission she improved and ventilation was stopped after 8 days. Twenty three days following admission, serum CMV viral load was undetectable by PCR. She was prescribed Valganciclovir prophylaxis for 6 weeks. Her CMV titres were monitored weekly for these 6 weeks, then fortnightly for a further 3 months, and these showed no signs of viral reactivation. An 8-week course of Atovaquone as prophylaxis against PJP was also prescribed.
2. Discussion Alemtuzumab is a humanised monoclonal antibody targeting CD52 that causes temporary but profound depletion of B and T lymphocytes and leads to long-lasting changes in adaptive immunity. It is significantly more effective than interferon beta 1a in reducing clinical and radiological disease activity in patients with RRMS who are treatment naïve (Cohen et al., 2012) or relapse on first-line disease-modifying therapy (Coles et al., 2012). However, the drug's substantial therapeutic efficacy comes at a significant safety cost. Infusion-related reactions are anticipated and almost ubiquitous, but generally managed without complications using antipyretics, anti-histamines, nebulisers and steroids. Much has been published about patients’ likelihood of developing secondary autoimmune disorders following treatment with alemtuzumab (Lisa et al., 2012; Cossburn et al., 2011; Jones et al., 2009) with a third of patients developing thyroid dysfunction (Coles et al., 1999; Daniels et al., 2013) and smaller numbers developing immune thrombocytopaenic purpura (≤2%) or anti-glomerular basement membrane disease (≤0.1%) (Cuker et al., 2011; Clatworthy et al., 2008; Meyer et al., 2013). 2
Multiple Sclerosis and Related Disorders 14 (2017) 1–3
K. Yann et al.
Declaration of conflicting interests
multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). The J. Clin. Investig. 119 (7), 2052. Coles, Alasdair J., et al., 1999. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. The Lancet 354 (9191), 1691–1695. Daniels, Gilbert H., et al., 2013. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. The J. Clin. Endocrinol. Metab. 99 (1), 80–89. Cuker, Adam, et al., 2011. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood 118 (24), 6299–6305. Clatworthy, Menna R., Elizabeth, F. Wallin, David, R. Jayne, 2008. Anti–glomerular basement membrane disease after Alemtuzumab. New Engl. J. Med. 359 (7), 768–769. Meyer, David, et al., 2013. Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing–remitting multiple sclerosis. Multiple Scler. Relat. Disord. 2 (1), 60–63. Coles, A.J., 2013. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics 10 (1), 29–33. Willis, M.D., et al., 2016. Alemtuzumab for multiple sclerosis: long term follow-up in a multi-centre cohort. Mult. Scler. J. 22 (9), 1215–1223. Tuohy, Orla, et al., 2015. Alemtuzumab treatment of multiple sclerosis: long term safety and efficacy. J. Neurol. Neurosurg. Psychiatry 86, 208–215.
The authors declare that there is no conflict of interest. References The ARDS definition task force acute respiratory distress syndrome: the Berlin definition, 2012. JAMA, 307 (23), 2526–2533. Cohen, Jeffrey A., et al., 2012. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. The Lancet 1819–1828. Coles, Alasdair J., et al., 2012. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. The Lancet 1829–1839. Lisa, Costelloe, Jones, Joanne, Coles, Alastair, 2012. Secondary autoimmune diseases following alemtuzumab therapy for multiple sclerosis. Expert Rev. Neurother. 12 (3), 335–341. Cossburn, M., et al., 2011. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 77 (6), 573–579. Jones, Joanne L., et al., 2009. IL-21 drives secondary autoimmunity in patients with
3
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Case report
MARK
Acute respiratory distress syndrome following alemtuzumab therapy for relapsing multiple sclerosis Keh Yann, Jackson Fran, Sharaf Nazar, Mihalova Tatiana, Talbot Paul, Rog David, Pace Adrian
⁎
Greater Manchester Multiple Sclerosis Group, Salford Royal NHS Foundation Trust, UK
A R T I C L E I N F O
A B S T R A C T
Keywords: Alemtuzumab Multiple sclerosis Pneumocystis jirovecii Cytomegalovirus ARDS
We present the case of a 54 year old woman with known relapsing-remitting multiple sclerosis who presented with acute respiratory deterioration five weeks after a first course of alemtuzumab. Imaging showed bilateral ground glass changes and extensive investigations confirmed chest infection with dual pathogens - Pneumocystis jirovecii and Cytomegalovirus. She responded to standard anti-PJP and CMV therapy and was discharged on oral prophylaxis. Opportunistic infections in the weeks immediately following alemtuzumab therapy remain an uncommon complication but one that requires clinical vigilance, careful monitoring and appropriate prophylactic therapy.
1. Case report A 54 year old woman received a 5-day course of intravenous alemtuzumab in May 2015 for active relapsing-remitting multiple sclerosis (RRMS). She was diagnosed with RRMS in 2004 and started immediately on Betaferon. In October 2011 she was switched to Copaxone due to ongoing relapses but changed again to Avonex in August 2012 after experiencing a delayed allergic-type reaction. In March 2015 she suffered a disabling relapse with left hemiparesis, spasticity and deteriorating mobility. Her last relapses on treatment had been in February 2014 and October 2012. In view of ongoing disease activity, alternative treatment options were discussed and she chose alemtuzumab. Past medical history included laparoscopic right hemicolectomy with ileocolonic anastomosis in 2013 for terminal ileal neuroendocrine tumour (grade 3 carcinoid), asthma, hysterectomy, and cholecystectomy complicated by left popliteal DVT and pulmonary embolus. Her family history was unremarkable. She did not smoke and had not recently travelled abroad. Following discharge she developed malaise, fatigue, nausea, anorexia and sweating. Monitoring blood tests 4 weeks post-treatment showed lymphopaenia (0.6×103/mm3), microcytosis (79.3 fL) and raised ALP (133U/L). Five weeks post-treatment she presented to our emergency department with dyspnoea, cough and haemoptysis. On examination she was pyrexial (38.4 °C), tachypnoeic (20 respirations/ min), hypotensive (BP 98/60 mmHg) and tachycardic (90 bpm). Oxygen saturation dropped to 72% on minimal exertion. There was ⁎
no meningism, lymphadenopathy, rash, jaundice or cyanosis. Chest auscultation revealed bibasal inspiratory crepitations. Neurological and abdominal examinations were unremarkable. Renal, liver and thyroid function tests, glucose, clotting screen, D-dimer and calcium were normal. Arterial blood gases showed Type 1 respiratory failure (pCO2 4.1 kPa; pO2 8.2 kPa) on air, full blood count confirmed lymphopaenia (0.6×109/L) and CRP was raised (38 mg/L; N≤5 mg/L). Chest X-ray showed bibasilar reticulonodular shadowing. She was admitted and treated empirically with intravenous acyclovir, co-amoxiclav and clarithromycin for presumed pneumonia. The next day later she remained febrile and became increasingly dyspnoeic. Her antibiotics were changed to intravenous benzylpenicillin, doxycycline and clindamycin, and she was started on Primaquine to cover for Pneumocystis jiroveci pneumonia (PJP). Computed Tomography pulmonary angiography(CTPA) excluded embolism but showed bilateral patchy consolidation and ground glass opacities without lymphadenopathy or pleural effusion (Fig. 1). Due to worsening oxygenation despite non-invasive respiratory support, she was transferred to intensive care for intubation and ventilation on the fourth day of admission. Bronchoalveolar lavage (BAL) washings were sent for microbiological and virology studies. Her level of arterial hypoxaemia (with a calculated pO2/FiO2 ratio of 292 mmHg) and the presence of bilateral radiographic changes fulfilled Berlin criteria for acute respiratory distress syndrome (ARDS) (The ARDS Definition Task Force Acute respiratory distress syndrome: the Berlin definition, 2012) At this point an inflammatory pneumonitis/ alveolitis was suspected as the underlying cause and she was given intravenous methylprednisolone (1 g daily for 3 days), followed by a
Correspondence to: Department of Neurology, Level 3, Humphrey Booth Building, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, United Kingdom. E-mail address: [email protected] (P. Adrian).
http://dx.doi.org/10.1016/j.msard.2017.03.001 Received 20 February 2017; Accepted 5 March 2017 2211-0348/ Crown Copyright © 2017 Published by Elsevier B.V. All rights reserved.
Multiple Sclerosis and Related Disorders 14 (2017) 1–3
K. Yann et al.
Fig. 1. CTPA imaging showing patchy bilateral ground glass changes.
Another risk is the potential exposure of patients receiving alemtuzumab to opportunistic infection in initial months following treatment, when B and T lymphocyte populations are profoundly depleted. To some extent, concern has been assuaged following clinical trial safety outcomes, where infections were more common following alemtuzumab compared to interferon beta 1a but predominantly mild-moderate in severity (Coles, 2013). Reasons proposed for this include preservation of haematopoietic stem cells (which do not express CD52) in bone marrow and thymus and lesser reduction in central memory, effector memory and regulatory T-cell numbers, suggesting innate memory responses remain intact following treatment. A further possibility is the drug's administration as a single short course, which allows B- and Tlymphocyte populations to reconstitute almost completely within months. Despite these considerations, patients with MS are still vulnerable to opportunistic infections from external agents or reactivation of dormant viruses in the first weeks following treatment with alemtuzumab (Willis et al., 2016). In clinical trials an increased risk of herpetic infections was noted (Willis et al., 2016; Tuohy et al., 2015), and acyclovir is now given during and for 28 days following treatment. While 200 mg BD of acyclovir was given in the CARE-MS trials, the authors’ practice is to prescribe 400 mg BD as local microbiological advice suggests that this conveys better prophylaxis. To the authors’ knowledge, this is the first case of ARDS secondary to alemtuzumab in the context of MS therapy described in the literature. It highlights the need for vigilance by both patients and physicians to systemic symptoms early after therapy, even when nonspecific, as these may indicate emergent opportunistic infections. This case is unusual in that the patient's respiratory deterioration was due to dual infection with PJP and CMV. As alemtuzumab use in RRMS becomes increasingly common, it remains to be seen whether further associations with these infections will emerge, and if this will warrant a change in recommendations for prophylaxis in the future.
steroid taper. Urine Legionella and Pneumococcal antigens, bacterial and TB cultures and HIV tests were negative. Virology and PCR studies were negative for influenza A and B, RSV, mycoplasma, metapneumovirus, adenovirus, rhinovirus and parainfluenza virus types 1–3, but confirmed the presence of Pneumocystis jirovecii. Blood PCR was also strongly positive for CMV (13008 IU/ml) and the BAL sample yielded 1.4 million copies of CMV/ml, consistent with active infection. She received a 2 week course of IV ganciclovir. By the second week of admission she improved and ventilation was stopped after 8 days. Twenty three days following admission, serum CMV viral load was undetectable by PCR. She was prescribed Valganciclovir prophylaxis for 6 weeks. Her CMV titres were monitored weekly for these 6 weeks, then fortnightly for a further 3 months, and these showed no signs of viral reactivation. An 8-week course of Atovaquone as prophylaxis against PJP was also prescribed.
2. Discussion Alemtuzumab is a humanised monoclonal antibody targeting CD52 that causes temporary but profound depletion of B and T lymphocytes and leads to long-lasting changes in adaptive immunity. It is significantly more effective than interferon beta 1a in reducing clinical and radiological disease activity in patients with RRMS who are treatment naïve (Cohen et al., 2012) or relapse on first-line disease-modifying therapy (Coles et al., 2012). However, the drug's substantial therapeutic efficacy comes at a significant safety cost. Infusion-related reactions are anticipated and almost ubiquitous, but generally managed without complications using antipyretics, anti-histamines, nebulisers and steroids. Much has been published about patients’ likelihood of developing secondary autoimmune disorders following treatment with alemtuzumab (Lisa et al., 2012; Cossburn et al., 2011; Jones et al., 2009) with a third of patients developing thyroid dysfunction (Coles et al., 1999; Daniels et al., 2013) and smaller numbers developing immune thrombocytopaenic purpura (≤2%) or anti-glomerular basement membrane disease (≤0.1%) (Cuker et al., 2011; Clatworthy et al., 2008; Meyer et al., 2013). 2
Multiple Sclerosis and Related Disorders 14 (2017) 1–3
K. Yann et al.
Declaration of conflicting interests
multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). The J. Clin. Investig. 119 (7), 2052. Coles, Alasdair J., et al., 1999. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. The Lancet 354 (9191), 1691–1695. Daniels, Gilbert H., et al., 2013. Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis. The J. Clin. Endocrinol. Metab. 99 (1), 80–89. Cuker, Adam, et al., 2011. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood 118 (24), 6299–6305. Clatworthy, Menna R., Elizabeth, F. Wallin, David, R. Jayne, 2008. Anti–glomerular basement membrane disease after Alemtuzumab. New Engl. J. Med. 359 (7), 768–769. Meyer, David, et al., 2013. Case report of anti-glomerular basement membrane disease following alemtuzumab treatment of relapsing–remitting multiple sclerosis. Multiple Scler. Relat. Disord. 2 (1), 60–63. Coles, A.J., 2013. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics 10 (1), 29–33. Willis, M.D., et al., 2016. Alemtuzumab for multiple sclerosis: long term follow-up in a multi-centre cohort. Mult. Scler. J. 22 (9), 1215–1223. Tuohy, Orla, et al., 2015. Alemtuzumab treatment of multiple sclerosis: long term safety and efficacy. J. Neurol. Neurosurg. Psychiatry 86, 208–215.
The authors declare that there is no conflict of interest. References The ARDS definition task force acute respiratory distress syndrome: the Berlin definition, 2012. JAMA, 307 (23), 2526–2533. Cohen, Jeffrey A., et al., 2012. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. The Lancet 1819–1828. Coles, Alasdair J., et al., 2012. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. The Lancet 1829–1839. Lisa, Costelloe, Jones, Joanne, Coles, Alastair, 2012. Secondary autoimmune diseases following alemtuzumab therapy for multiple sclerosis. Expert Rev. Neurother. 12 (3), 335–341. Cossburn, M., et al., 2011. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 77 (6), 573–579. Jones, Joanne L., et al., 2009. IL-21 drives secondary autoimmunity in patients with
3