key: cord-1042660-6ybpwash authors: Matías-Guiu, Jorge; Montero-Escribano, Paloma; Pytel, Vanesa; Porta-Etessam, Jesús; Matias-Guiu, Jordi A. title: Potential COVID-19 infection in patients with severe multiple sclerosis treated with alemtuzumab date: 2020-06-11 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2020.102297 sha: 9a2b23717aae8495a192207dde3779eb9f1e7667 doc_id: 1042660 cord_uid: 6ybpwash BACKGROUND: Management of disease-modifying therapies in Multiple Sclerosis (MS) during the COVID-19 pandemic is a controversial issue. Alemtuzumab is an immunosuppressive drug that induces lymphocytes depletion. In this study, we aimed to evaluate the frequency and severity of COVID-19 in a case series of patients treated with alemtuzumab in our center. METHODS: Ten patients with a diagnosis of relapsing-remitting MS were phoned and asked about symptoms suggestive and COVID-19 using a semi-structured questionnaire. RESULTS: The mean age was 43.7 ± 9.65 years old, and 8 (80%) were females. The mean time since disease diagnosis was 17.30 ± 8.59 years, and all were patients with relapsing-remitting MS. Mean time from the last dose of Alemtuzumab was 9.80 ± 6.64 months, and last lymphocyte count was 760 ± 231 / μL. Two patients (20%) developed symptoms highly suggestive of COVID-19. Disease duration was 2 and 7 days. None patient required hospital admission. Patients with COVID-19 symptoms had longer clinical course of MS. Conversely, we did not find statistically significant differences regarding age, EDSS, last lymphocyte count, and months since the last dose of alemtuzumab administered between patients having or not symptoms of COVID-19. CONCLUSIONS: Our data suggest that patients receiving alemtuzumab showed very mild symptoms of COVID-19. We speculate that immune reconstitution induced by treatment may induce positive changes in the immune system in the defense against SARS-CoV2. Further research about alemtuzumab and their role in COVID-infection is necessary to confirm these preliminary findings. Since the onset of the COVID-19 pandemic, the management of disease-modifying therapies is a controversial issue in patients with MS and other autoimmune disorders. In theory, and using the information available from other viral infections, patients under immunosuppressive drugs could be more susceptible to the COVID-19 infection or have a worse outcome. Thus, first recommendations suggested the temporary delay of some of these therapies, especially those associated with lymphocytes depletion, such as rituximab, ocrelizumab, or alemtuzumab (Brownlee et al 2020; Coles et al., 2020; Giovannoni et al., 2020; Li et al., 2020; Novi et al., 2020; Quinti et al., 2020) . However, preliminary observations in MS, and specifically in patients receiving anti-CD20 rituximab and ocrelizumab, suggests a low severity of the infection (Giovannoni, 2020; Montero-Escribano et al., 2020; Sormani et al., 2020) . To date there is limited data about alemtuzumab and COVID-19 infection (Sormani et al., 2020) . Alemtuzumab is a humanized IgG1 antibody targeting the glycophosphatidylinositol-anchored CD52 protein expressed in lymphocytes (Li et al. 2018) . It induces depletion of cells expressing CD52 through antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and pro-apoptotic pathways. Consequently, alemtuzumab causes a profound B-and T-cell depletion (Cohen et al., 2012; Coles et al., 2012; Hartung et al., 2015) . Alemtuzumab is currently used in patients with severe Multiple Sclerosis (MS), and some transplants (Bhowmick et al., 2016) . Because patients with Alemtuzumab are also those with more severe forms of the disease, higher susceptibility to COVID-19 effects could even be more hazardous. In this study, we aimed to evaluate the frequency and severity of COVID-19 in a case series of patients treated with alemtuzumab in our center. This is a single-center observational case series study evaluating the frequency and severity of COVID-19 among patients with MS (Thompson et al., 2018) followed up in the Department of Neurology of a tertiary hospital in Madrid, Spain. All patients were contacted by phone from 5 th to 8 th May 2020 , when confirmed cases in the Region of Madrid accounted for 64,333. Because of the Government's decision of testing with RT-PCR only in patients requiring hospital admission, cases with suggestive symptoms were also considered. The hospital's Ethics Committee approved the research protocol (reference 20/242-E), and patients gave oral informed consent. Demographic and clinical characteristics about MS were obtained from the last regular consultation during December 2019-February 2020. The neurologist responsible for the care of each patient since at least five years contacted by phone with each patient. A semi-structured interview was conducted using a questionnaire including: relapses during the pandemic, clinical characteristics of these relapses, pseudo-relapses, and other symptoms associated to MS; symptoms suggestive of COVID-19, characteristics, duration, consequences (hospital admission), and RT-PCR performance. The same questions about COVID-19 were also asked to the people living with MS patients or close contacts directly to the relatives when possible, or through the patients with MS. Average duration of each interview was 20 minutes. Statistical analysis was conducted using SPSS Statistics v20. Descriptive results are shown as mean ± standard deviation or median (interquartile range), and frequency (percentage). We used the Mann-Whitney U test to compare two groups (patients with and without COVID-19 symptoms). A p-value <0.05 was considered statistically significant. We included ten patients treated with alemtuzumab at the onset of the pandemic. The mean age was 43.7 ± 9.65 years old, and 8 (80%) were females. The mean time since disease diagnosis was 17.30 ± 8.59 years, and all were patients with relapsing-remitting MS. Mean time from the last dose of alemtuzumab was 9.80 ± 6.64 months, and last lymphocyte count was 760 ± 231 / μL. Two patients (20%) developed symptoms highly suggestive of COVID-19. The first patient was a 54 years-old woman with an EDSS of 6.5 who presented fever and diarrhea for two days and had at least two relatives also affected. One of them was her husband, who presented fever, cough, fatigue, and pleuritic chest pain for three weeks at the same time. The second case was a 51 years-old female with EDSS 6.5 that developed fever, ageusia, anosmia, asthenia, headache, and diarrhea for one week. He had no relatives affected. No patient required hospital admission, and both cases were not assessed by RT-PCR. However, the first case had a positive serological study (IgG) one month later. The main demographic and clinical characteristics are shown in Table 1 . In addition, one case did not show any symptom despite her husband presented fever and cough for more than one week with RP-PCR positive for COVID-19. We compared baseline characteristics of patients showing or not COVID-19 symptoms. We did not find statistically significant differences regarding age (52.50 ± 2.12 in COVID-19 vs. 41.50 ± 9.56 in non-COVID-19, U=2.0, p=0.116), sex (100% of females vs 75% , X 2 =0.625, p=0.622), EDSS (U=7.0, p=0.785), last lymphocyte count (750 ± 353 vs. 762 ± 226 U=7.5, p=0.895), and months since last dose administered (13 ± 0 vs 9.0 ± 7.28, U=3.0, p=0.185). Patients with COVID-19 symptoms had longer clinical course of MS (29.50 ± 9.19 vs. 17.30 ± 8.59, U=0.0, p=0.034) The use of immunosuppressive therapies in patients with autoimmune disorders is a major concern during the COVID-19 pandemic. In this regard, several authors recommend conservative approaches to minimize the risk of severe SARS-CoV2 infection in patients with MS . However, the potential negative impact of immunosuppressive therapies in patients with MS and COVID-19 have been questioned according to the increasing knowledge of the pathophysiology of COVID-19 infection and the preliminary evidence in MS patients . One of the worrisome drugs in the setting of COVID-19 is alemtuzumab, which produces a profound depletion of circulating B-and T-cells after the administration. Lymphocytes repopulated in the following months, and B-cells usually recover completely within six months, while T-cells recover more slowly and do not return to baseline counts by 12 months after treatment administration. Our study found two patients probably infected by COVID-19 that had received the last dose one year before and showed mild and short symptoms of the disease. Furthermore, one case was not infected or did not show any symptoms despite living with a relative infected with RT-PCR confirmation. These findings, although very preliminary, may suggest that patients treated with alemtuzumab did not show a higher risk of COVID-19 infection or greater severity. Likewise, patients with MS and alemtuzumab seemed to show milder and shorter forms of COVID-19 in comparison to their relatives. Alemtuzumab produces a lymphocyte reconstitution of the immune system, with the development of a new generation of lymphocytes from a new lineage (Hartung et al., 2015) , starting with regulatory T-cells, but with a relevant role of memory lymphocytes. Perhaps the lymphocyte reconstitution induced by alemtuzumab, including changes in composition, phenotype, and function of lymphocytes, may confer a potential resistance of this new lineage to the virus or avoiding the cytokine storm associated with life-threatening complications such as cardiac dysfunction, respiratory failure, and coagulopathy . Furthermore, immune changes induced by alemtuzumab, which has been compared with a "reset" of the immune system, might be compared with the case of children infected by SARS-Cov2 (Zhang et al., 2013) . In children, the immune system and T-cells seem to be more efficient in the response against SARS-Cov2 with excellent outcomes (Dong et al., 2020) . In addition, children are less prone to the raise of pro-inflammatory cytokines including IL-6 that leads to the development of cytokine storm and pulmonary inflammation . Interestingly, patients treated with alemtuzumab also show lower levels of IL-6 (Zhang et al., 2013) . On the one hand, these findings suggest that alemtuzumab should be safe in the current context. The only baseline factor associated with the infection was the time since diagnosis, an aspect that would suggest that patients with longer MS might be more susceptible to the infection, although this issue should be replicated in other samples because all patients were not exposed to the same risk of contagion. On the other hand, although we have no evidence of patients recently treated and exposed to SARS-CoV2 infection, we may hypothesize about a potential role of alemtuzumab in the acute management of cytokine storm of COVID-19. In this regard, tocilizumab, an IL-6 inhibitor, is being tested for the treatment of severe COVID-19 with promising results (Alattar et al., 2020) . However, the potentially affected individuals reported had demographics associated with recovery (Guan et al. 2020; Myers et al. 2020) Our study has some limitations. First, our sample size is limited, and none patient recently treated with alemtuzumab was infected. Indeed, none of our patients received alemtuzumab during the pandemic, and those patients that developed COVID-19 showed partial or complete lymphocyte reconstitution in the last count. Larger and multicenter studies would be necessary to confirm these findings and to evaluate the safety of patients receiving alemtuzumab during the pandemic. The definition of the risk of COVID-19 in the different immunological phases after treatment with alemtuzumab may have important implications in the current situation to optimize the therapeutic management as well as the recommendations about quarantine and self-protection for patients with MS. Second, none MS patient was evaluated with RT-PCR. However, all patients had highly suggestive clinical symptoms of COVID-19 and several relatives affected in familial clusters as in most COVID-19 cases. In addition, the absence of RT-PCR may reinforce our results because patients had no laboratory confirmation of the infection due to mild symptoms not requiring hospital admission. In conclusion, our study suggests that alemtuzumab seems to be safe in the context of the COVID-19 pandemic. Furthermore, we speculate whether alemtuzumab may even be a therapeutic option for the COVID-19 infection itself, given the mechanism of action generating a reconstituted immune system more resistant to the virus and reducing the risk of the cytokine storm. Further research is necessary to confirm our findings. Funding: none. The authors have no conflicts of interest to declare. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic Alemtuzumab as Antirejection Therapy: T Cell Repopulation and Cytokine Responsiveness Treating multiple sclerosis and neuromyelitis optica spectrum disease during the COVID-19 pandemic Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial ABN Guidance on the Use of Disease-Modifying Therapies in Multiple Sclerosis in Response to the Threat of a Coronavirus Epidemic Epidemiology of COVID-19 among Children in China The COVID-19 pandemic and the use of MS disease-modifying therapies Anti-CD20 Immunosuppressive Disease-Modifying Therapies and COVID-19 Clinical characteristics of coronavirus disease 2019 in China Alemtuzumab: a new therapy for active relapsingremitting multiple sclerosis Severe acute respiratory syndrome (SARS) in neonates and children Clinical pharmacology of alemtuzumab, an anti-CD52 immunomodulator, in multiple sclerosis Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients Management of neurological care during the COVID-19 pandemic Anti-CD20 and Covid-19 in Multiple Sclerosis and related disorders: a case series of 60 patients from Madrid, Spain Characteristics of hospitalized adults with COVID-19 in an integrated health care system in California COVID-19 in a MS Patient Treated With Ocrelizumab: Does Immunosuppression Have a Protective Role? A possible role for B cells in COVID-19?: Lesson from patients with Agammaglobulinemia The COVID-19 vaccine development landscape Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria Study Group on COVID-19 infection in multiple sclerosis, 2020. An Italian programme for COVID-19 infection in multiple sclerosis The risk of children hospitalized with severe COVID-19 in Wuhan Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from jordimatiasguiu@hotmail.com