key: cord-1034899-ck7wretx authors: Valencia-Sanchez, Cristina; Wingerchuk, Dean M. title: A fine balance: Immunosuppression and immunotherapy in a patient with multiple sclerosis and COVID-19 date: 2020-05-08 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2020.102182 sha: fc59e5e1385a24e22a160b88f3b8c256e0178f72 doc_id: 1034899 cord_uid: ck7wretx Abstract Background : Treatment decisions in patients with multiple sclerosis (MS) during the coronavirus disease 2019 (COVID-19) pandemic are challenging. It is not known whether and how various disease modifying therapies, especially immunosuppressive drugs, affect COVID-19 risk and disease course. Methods : Case report Results : We report a fingolimod-treated MS patient who developed severe COVID-19 but recovered after treatment with tocilizumab. Conclusion : This report suggests that a brief course of tocilizumab for the treatment of severe COVID-19 may be effective while not aggravating pre-existing MS. Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 and is currently pandemic. COVID-19 appears to have a mild course in most people but individuals over 50 years of age and those with pre-existing conditions may fare worse with relatively high rates of need for ventilatory assistance and subsequent death. As a novel disease entity without herd immunity, an available vaccine, or proven therapy, COVID-19 presents additional challenges for patients taking immunosuppressant drugs, including some multiple sclerosis (MS) disease modifying therapies (DMTs). Immunosuppressed patients are plausibly at higher risk for a more severe COVID-19 course although this is not established. Guidance for management of MS DMTs during the pandemic have been issued by national professional societies and patient organizations but is largely speculative as little has yet been reported on COVID-19 course and outcomes in MS patients with or without use of DMTs (Brownlee et al., A contrasting hypothesis concerns the potential benefit of some immunotherapies for COVID-19 infection, proposing a protective role via limitation of the hyperactive inflammatory response (cytokine release syndrome (CRS) or "cytokine storm") associated with clinical deterioration in COVID-19. A recent report of a MS patient who did well despite COVID-19 infection while on the B cell-depleting drug ocrelizumab illustrates this general hypothesis (Novi et al., 2020) . More specifically, tocilizumab, a humanized monoclonal antibody that targets the interleukin-6 (IL-6) receptor, has been reported to improve outcomes for patients with severe COVID-19 infection and is the subject of controlled trials (Luo et al., 2020) . We present a patient with MS who developed COVID-19 while treated with fingolimod. After suspension of fingolimod, she developed CRS and acute respiratory distress syndrome (ARDS) and was successfully treated with tocilizumab. A 58-year-old female presented to the emergency department with three days of fever and dry cough. Her son had previously developed similar symptoms. She was diagnosed with relapsing MS in 2007 and was previously treated with interferon beta 1a, glatiramer acetate, and natalizumab; she had been taking fingolimod since 2011. Her most recent examination showed a stable Expanded Disability Status Scale score of 6, and there was no evidence of disease activity for several years. Her past history included migraine, diabetes mellitus, hypertension, hyperlipidemia, obesity, and transient ischemic attack. Upon presentation, oxygen saturation was 95% and she was afebrile. PCR for SARS-CoV-2 on nasal swab was positive. Chest x-ray was unremarkable. She was advised to self-isolate at home and take acetaminophen. She returned 5 days later with worsening dyspnea, and chest x-ray showed multifocal pneumonia. Chest computed tomography showed multiple bilateral peripheral bilateral ground glass opacities. Absolute lymphocyte count (ALC) was 0.33 x10 9 /L (figure 1), similar to five months prior to hospitalization (0.3 x10 9 /L) and the range since treatment onset (0.19-0.39x10 9 /L). She had elevated C-reactive protein (CRP), ferritin and lactate dehydrogenase, and D-dimer was normal (figure 2). The patient was admitted and hydroxychloroquine and azithromycin were initiated. Fingolimod was discontinued. Two days after admission, IL-6 was elevated at 23.6 pg/mL (normal <1.8), and inflammatory markers were higher (figures 2 and 3). Three days later, the patient developed increasing oxygen needs and chest X-ray revealed worsening airspace opacities in both lungs. She required intubation due to respiratory failure and was transferred to the intensive care unit (ICU). She received one dose of intravenous tocilizumab 600 mg. She did not receive corticosteroids. One day after tocilizumab, IL-6 peaked to >400 pg/mL. Her lymphocyte count normalized 9-12 days after fingolimod discontinuation. While in the ICU, she also required hemodynamic support with vasopressors. After 10 days, she was extubated. Over the following four days, she continued to improve clinically, CRP level normalized and IL-6 improved. She was discharged 4 days post-extubation. Fingolimod was reinitiated prior to discharge, 18 days after discontinuation. At the follow up video visit one week after discharge, the patient continued self-isolation, and she reported hyposmia and dysgeusia. We describe a fingolimod-treated MS patient who developed severe COVID-19, ARDS and CRS that responded to tocilizumab therapy. Fingolimod was discontinued upon hospital admission owing to concern that immunosuppression may worsen COVID-19. whereas another patient with RA and MS was treated with anti-IL-6 therapy for more than 5 years without experiencing a MS exacerbation (Sato et al., 2014) . Although these reports suggest that IL-6 inhibition could cause or trigger CNS inflammatory demyelination, a report describes an adolescent with a tumefactive cervical demyelinating lesion who was successfully treated with tocilizumab (Hoshino et al., 2020) . Therefore, the MS-related implications of both acute and chronic IL-6 therapy remain uncertain. Our report illustrates the complexity of interpreting the effects of adding or suspending immunotherapies in MS patients who develop COVID-19. Some monoclonal antibodies, such as the anti-CD19 ocrelizumab and the anti-CD52 alemtuzumab, have cell depleting effects that last many months and are not reversible. In contrast, suspension of fingolimod results in a rapid return of sequestered lymphocytes to the peripheral circulation, likely reversing most of its immunosuppressive properties and allowing opportunity for intervention. The risk of "rebound" MS disease after fingolimod discontinuation is delayed 2-4 months and is probably mitigated by restarting the drug after COVID-19 recovery, as in our case. Our case also suggests that a brief course of tocilizumab for the treatment of severe COVID-19 may be effective while not aggravating pre-existing MS. This is also likely the case for COVID-19 that develops in patients with neuromyelitis optica spectrum disorder, for which IL-6 inhibition has demonstrable efficacy for attack prevention (Yamamura et al., 2019) . Ongoing registries will provide more insight about the outcomes of patients with MS who develop COVID-19 while taking various DMTs and who receive other immunotherapies. Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role? 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