key: cord-0866528-1d97intu authors: Etemadifar, Masoud; Sedaghat, Nahad; Aghababaee, Ali; Kargaran, Parisa K; Maracy, Mohammad Reza; Ganjalikhani-Hakemi, Mazdak; Rayani, Milad; Abhari, Amir Parsa; Khorvash, Reza; Salari, Mehri; Nouri, Hosein title: COVID-19 and the Risk of Relapse in Multiple Sclerosis Patients: A Fight with No Bystander Effect? date: 2021-03-20 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2021.102915 sha: 90d321d098d86fdeb75a151fef441f0a25263988 doc_id: 866528 cord_uid: 1d97intu Background: COVID-19 is speculated to increase the likelihood of relapsing-remitting multiple sclerosis (RRMS) exacerbation. Objective: To investigate the association between contraction of COVID-19 and incidence of acute MS attacks in RRMS patients six months post-infection. Methods: This retrospective cohort study compares the risk of relapse in RRMS patients with (n=56) and without COVID-19 (n=69). Incidence of relapse was recorded for six-month following contraction of COVID-19. Incidence of RRMS exacerbation in patients with COVID-19 was compared to patients without COVID-19 (the independent control group) and the same patients six months prior to the COVID-19 pandemic. Results: A lower incidence rate of RRMS exacerbation was observed in patients that contracted COVID-19 than in patients who did not contract COVID-19 (incidence rate ratio: 0.275; p=0.026). Self-controlled analysis showed no significant difference in relapse rates before the COVID-19 pandemic and after contracting COVID-19 (p=0.222). The relapse risk was not different between patients who had been hospitalized due to COVID-19 severity and those who had not (p=0.710). Conclusion: COVID-19 contraction may not increase the risk of acute MS attacks shortly following contraction. We hypothesize that COVID-19-associated lymphopenia may partly preclude the autoreactive memory cells from expansion and initiating relapses through a so-called bystander effect of COVID-19 infection. The Coronavirus Disease-2019 (COVID-19) pandemic has rapidly spread across the globe, with the number of confirmed cases surpassing 100 million. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the responsible microbial agent, is an enveloped positive-sense single-stranded RNA virus and categorized in the beta coronavirus family (1) . COVID-19 can be clinically manifested through a wide range of symptoms with different degrees of severity from asymptomatic to severe. The majority of the infected individuals experience a relatively manageable disease course and do not require hospitalization or intensive care (2) . Since the onset of the COVID-19 outbreak, multiple sclerosis (MS) patients receiving diseasemodifying therapies (DMTs) were considered at a higher risk for experiencing severe disease courses. MS is a chronic autoimmune-mediated neuroinflammatory disease of the central nervous system (CNS), characterized by inflammation, demyelination, gliosis, and neuroaxonal loss (3) . MS is considered a multifactorial disease of unknown etiology, impacted by genetics and environmental factors, including viral infections (4) . Certain viral infections that induce severe systemic inflammatory reactions are associated with a higher risk of MS relapses shortly following the infection (5) (6) (7) (8) (9) (10) (11) . It is suggested that the proinflammatory milieu secondary to activation of host cellular and humoral immunity to the viral infection may promote migration of previously activated autoreactive T cells across the blood-brain barrier (BBB), resulting in CNS inflammation and exacerbations in relapsing-remitting MS (RRMS) patients (12) . SARS-CoV-2, similar to its phylogenetically identical strains, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), can promote a proinflammatory immune profile, characterized by elevated circulating level of interleukin-6 (IL-6) in the majority of COVID-19 patients (13) (14) (15) . This hyperinflammatory immunological profile, along with the reportedly high frequency of psychological disturbances in RRMS patients as a result of the ongoing pandemic (16) , brought us to investigate the risk of relapses in RRMS patients following COVID-19 infection. To our knowledge, this is the first cohort study characterizing the risk of RRMS relapses following COVID-19. This retrospective cohort study included patients diagnosed with RRMS according to the 2017 McDonald criteria (17) , with a minimum disease duration of one year, as assessed by an expert neurologist. Participants were randomly selected from two groups 1) those who contracted COVID-19 during a period between March 1 st , 2020 and June 1 st , 2020 (COVID-19 group) and 2) RRMS patients who had no symptoms attributable to respiratory infections from February 1 st , 2020 to November 1 st , 2020 (non-COVID-19 group). Records of patients with COVID-19 were retrieved from two weeks before to six months after the onset of their COVID-19-related symptoms. Records from the patients without COVID-19 were retrieved from 6 months prior to November 1 st , 2020. For the self-control comparison, we retrieved all patients' records from the last six months before the COVID-19 pandemic emergence in Iran, using the Isfahan MS Clinic registry. The first case of COVID-19 in Iran, according to the national officials, was confirmed on February 19 th , 2020; therefore, the pre-COVID-19 pandemic period was defined as August 1 st , 2019 to January 30 th , 2020 (18) . Inclusion criteria for all participants of this study were 1) a definite diagnosis of RRMS, made by From March 2020, biweekly telephone surveys following the set guidelines were conducted to identify signs of a possible MS relapse. In case of a suspected exacerbation patients were requested to make an additional visit to the clinic within 3 days. MS relapse-associated symptoms were assessed on average every two months and on additional visits in case of suspected exacerbation. Graphical abstract of the study timelines is presented in Figure- 1. [ Figure-1] MS exacerbation was defined as development of a new neurologic abnormality, or worsening of a pre-existing one, for more than 24 hours. It must have been preceded by a stable or improving neurological state for at least 30 days, in the absence of concurrent fever, infection, or steroid withdrawal. COVID-19-related symptoms screened for included fever, anosmia, dysgeusia, myalgia, headaches, shortness of breath, diarrhea, nausea, sore throat, rhinorrhea, cough, vertigo, and chest pain. The ethical committee of Isfahan University of Medical Sciences approved this study and all patients signed informed consent letters for use of their clinical information. The Pearson Chi-Square test, paired samples t-test, and independent samples t-test were used to analyze the intergroup differences based on variable types. A generalized linear regression model (Poisson regression) was performed to predict the incidence rate ratio (IRR) of MS relapses during six months based on age, gender, type of treatment regimen, MS duration, and COVID-19 contraction. Conditional logistic regression analysis through a 1-1 matched (self-controlled) analysis was performed to assess the impact of COVID-19 infection on relapse number in COVID-19 group patients before the pandemic and after COVID-19 contraction. A significance criterion of 0.05 was set. Data were gathered and analyzed using IBM SPSS v.23 for macOS. 125 RRMS patients were included in this study, 56 of whom were included in the COVID-19 group and 69 in the non-COVID-19 group. There was no significant difference between the two groups in terms of mean age (p=0.746), while there was a higher proportion of females in the non-COVID-19 group (8.85:1 vs. 2.67:1, p=0.013). Demographic and clinical findings of the patients are presented in Table- 1. There was no significant difference in terms of Expanded Disability Status Scale (EDSS) scores (p=0.126) or disease durations (p=0.745) between the two groups. Of note, treatment regimens differed between the two groups (p=0.002) ( Table-1 ). Table- 1. The Poisson regression model showed that the incidence rate of acute MS relapses during six months was decreased by 72.5% in case of COVID-19 contraction (IRR: 0.275; 95% CI= 0.089 -0.855; p=0.026). Age, sex, MS duration, and different categories of applied DMTs did not have a significant effect in this regression model. One out of ten patients hospitalized due to severe COVID-19 experienced a relapse (1/10, 10%). Three out of 46 patients not hospitalized had a relapse episode after infection-associated symptoms onset (3/46, 6.98%). No difference in the relapse risk was observed between hospitalized and non-hospitalized patients (p=0.710). Patients of the two groups (i.e., the COVID-19 group and the non-COVID-19 group) were not significantly different concerning the number of MS attacks during the same last six months before the COVID-19 pandemic (14.29%, 8/56, in the COVID-19 group vs. 14.49%, 10/69, in the non-COVID-19 group, p=0.976). The difference between the frequency of relapses in the COVID-19 group during six months before the pandemic and six months after their infection with SARS-CoV-2 was not significant (14.29%, 8/56 before the pandemic vs. 7.14%, 4/56 after contracting COVID-19, p=0.222). Clinical manifestations of the relapses in the COVID-19 group in both timelines are presented in table-2. Conditional logistic regression for 1-1 matched (self-controlled) assessment with MS relapses as the outcome, showed no statistically significant effect of COVID-19 contraction (OR=0.462, 95% CI=0.131 to 1.632, p=0.230). [ This retrospective cohort study showed that COVID-19 contraction did not alter relapse rates in the same patients and that RRMS patients without clinical or laboratory findings suggestive of SARS-CoV-2 infection had a higher risk of experiencing MS relapses during the COVID-19 pandemic. Additionally, hospitalization due to COVID-19 severity was not associated with a change in the relapse rate in RRMS patients. Several studies in the literature suggest that viral respiratory tract infections increase the risk of MS exacerbations and relapses (5) (6) (7) (8) (9) (10) (11) . However, one should practice caution when interpreting the data from the currently existing literature. A considerable proportion of these studies date back to the pre-DMT era, and the investigated participants were not receiving the DMTs that are widely applied in modern practice (5, 6) . Further, no firm conclusions can be drawn from the studies on patients taking DMTs, concerning the effect of these therapies on infection-induced risk of relapse, with these papers either reporting contrary results (7, 9) or not being able to explore such effects due to the scant number of their patients who were not taking DMTs (10, 11) . Nevertheless, potential mechanisms for the suggested increased risk of relapse, following infection with viral agents, include the detection of viral epitopes, activation of host's T cells, and secretion of proinflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor (TNF)α. This proinflammatory profile increases the expression of endothelial adhesion molecules and increases BBB permeability, allowing for transmigration of previously activated, autoreactive Tcells across the BBB. Moreover, these proinflammatory cytokines contribute to the activation of CNS glial cells and macrophages, as well as expression of major histocompatibility complexes I/II and co-stimulatory molecules, promoting T cells reactivation and localized inflammation (12) . IL-1β and TNF-α may further maintain the migration and recruitment of autoreactive T cells into the sites of inflammation by increasing chemokine (e.g., CCL2 and CCL20) production by astrocytes and microglia cells (12, 19) . Some strains of human coronaviruses may be associated with stimulation of autoimmune demyelination in MS through toll-like receptors (TLRs) activation (20) . Nevertheless, there is limited data regarding an association between SARS-CoV-2 and MS progression or relapse. It was speculated that COVID-19 contraction could increase the risk of clinical exacerbations in patients with RRMS. Proposed mechanisms for this risk included 1) autoimmune response To our surprise, when compared to an independent control group (i.e., the non-COVID-19 group), RRMS patients who had contracted COVID-19 had significantly fewer relapse episodes (p=0.006). When analyzing the relapse rates between the COVID-19 group and the independent control group, we observed that contracting COVID-19 was associated with a 72.5% decrease in the IR of relapses (p=0.030). Possible confounding factors such as age, gender, treatment regimens, and MS duration had no effects on the relapse risk. Interestingly, RRMS patients in the COVID-19 group had similar relapse rates prior to COVID-19 contraction. IL-6 elevation is commonly observed in COVID-19 patients (14) . Increased levels of IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (G-CSF), interferon gamma-induced protein 10 (IP-10), CCL2, CCL3, and TNF-α, have been observed in most hospitalized patients with a relatively severe course of COVID-19 infection, experiencing cytokine storm syndrome (15, 26, 27) . Given this proinflammatory profile, increased risk of MS relapse is expected in patients with severe COVID-19 infection. However, relapse risk was not increased in either comparison type in this study (i.e., independent controls or self-controls). Moreover, no increased risk of relapse was observed in patients who had been hospitalized with a severe course of infection. and IFNγ) and up-regulated expression of T cell exhaustion markers (e.g., PD-1, Tim-3, and NKG2A) on the surface of these T cell subsets (31, 32) , and 3) COVID-19-induced disruption of proliferation and expansion of T cells, as the expression of some genes responsible in this regard (e.g., MAP2K7 and SOS1) are shown to be down-regulated in COVID-19 patients as long as they have not recovered from the infection (33) . We hypothesize that COVID-19-associated lymphopenia in RRMS patients may be partially involved in precluding the expansion and proliferation of autoreactive T cells. Thus, it may decrease the likelihood of cytokine-induced transmigration of these cells into the CNS parenchyma and initiation of acute MS exacerbations. Recently, Bonavita et al. have surveyed a large number of MS patients to assess perceived stress, depression, and perceived social support. Unfortunately, a significantly higher proportions of MS patients, compared to healthy controls, were depressed (43.1% vs. 23.1%; p<0.001), experienced high levels of stress (58% vs. 39.8%; p<0.001), and less perceived social support (p<0.001) (34) . These patients may experience high levels of chronic stress because of the pandemic, their clinical condition, and their immunosuppressive treatment regimens. Due to the retrospective nature of our study the psychological status of our patients could not be assessed during the recording of their relapses. Whether or not chronic stress predisposes MS patients to higher risks of developing relapses is controversial, partly due to the inter-study differences in terms of stress definition and measurement methods (35) . However, we speculate that this evident psychological stress on RRMS patients (16, 34) may have had an impact, at least partially, on the activity of their disease during this period, and it was more significant in patients who had not contracted COVID-19 during those times, probably facing chronically elevated levels of stress during the 9-10 months recorded in our study. Limitations of this study include its retrospective nature and the potential for errors in the registry system used for data collection. However, restrictive measures were taken to reduce such errors. Furthermore, assessing serological findings and psychological stimulators of MS relapses during the recording of relapse episodes was not possible. Our results suggest that COVID-19 infection, regardless of its severity, was not associated with an increased risk of relapse shortly following infection. However, should there be a long-term The authors received no specific funding for this work. A novel coronavirus from patients with pneumonia in China A comprehensive review of COVID-19 characteristics Immunopathology of multiple sclerosis Viral infections and multiple sclerosis Clinical viral infections and multiple sclerosis. The Lancet Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study Influence of infection on exacerbations of multiple sclerosis Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis Prospective study on the relationship between infections and multiple sclerosis exacerbations The risk of relapses in multiple sclerosis during systemic infections Monthly ambient sunlight, infections and relapse rates in multiple sclerosis The role of infections in multiple sclerosis Human immunopathogenesis of severe acute respiratory syndrome (SARS). Virus research Cytokines and COVID-19: friends or foes Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: comparison with SARS and MERS. Reviews in medical virology Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak. Multiple Sclerosis and Related Disorders Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report-31 Infection as an environmental trigger of multiple sclerosis disease exacerbation. Frontiers in immunology Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review COVID-19 and multiple sclerosis: predisposition and precautions in treatment. SN comprehensive clinical medicine Multiple sclerosis following SARS-CoV-2 infection. Multiple sclerosis and related disorders First case of SARS-COV-2 sequencing in cerebrospinal fluid of a patient with suspected demyelinating disease A first presentation of multiple sclerosis with concurrent COVID-19 infection. Eneurologicalsci A case series and literature review of multiple sclerosis and COVID-19: Clinical characteristics, outcomes and a brief review of immunotherapies Induction of proinflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome Dysregulated T cells in multiple sclerosis Lymphocyte subset (CD4+, CD8+) counts reflect the severity of infection and predict the clinical outcomes in patients with COVID-19 Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal transduction and targeted therapy Lymphopenia during the COVID-19 infection: What it shows and what can be learned. Immunology letters Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Frontiers in immunology Downregulated Gene Expression Spectrum and Immune Responses Changed During the Disease Progression in Patients With COVID-19 Perceived stress and social support in a large population of people with Multiple Sclerosis recruited online through COVID 19 pandemic Factors associated with relapses in relapsing-remitting multiple sclerosis: A systematic review and meta-analysis The authors have no conflict of interest to disclose.