key: cord-0888395-kn2gir2l
authors: Barzegar, Mahdi; Mirmosayyeb, Omid; Gajarzadeh, Mahsa; Afshari-Safavi, Alireza; Nehzat, Nasim; Vaheb, Saeed; Shaygannejad, Vahid; Maghzi, Amir-Hadi
title: COVID-19 Among Patients With Multiple Sclerosis: A Systematic Review
date: 2021-05-20
journal: Neurol Neuroimmunol Neuroinflamm
DOI: 10.1212/nxi.0000000000001001
sha: 461ae11a83545914c9940cdc169832ff8a5dfb22
doc_id: 888395
cord_uid: kn2gir2l

OBJECTIVE: We systematically reviewed the literature on COVID-19 in patients with multiple sclerosis (MS). METHODS: We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Google Scholar, and World Health Organization database from December 1, 2019, to December 18, 2020. Three conference abstract databases were also searched. We included any types of studies that reported characteristics of patients with MS with COVID-19. RESULTS: From an initial 2,679 publications and 3,138 conference abstracts, 87 studies (67 published articles and 20 abstracts) consisting of 4,310 patients with suspected/confirmed COVID-19 with MS met the inclusion criteria. The female/male ratio was 2.53:1, the mean (SD) age was 44.91 (4.31) years, the mean disease duration was 12.46 (2.27), the mean Expanded Disability Status Scale score was 2.54 (0.81), the relapsing/progressive ratio was 4.75:1, and 32.9% of patients had at least 1 comorbidity. The most common symptoms were fever (68.8%), followed by cough (63.9%), fatigue/asthenia (51.2%), and shortness of breath (39.5%). In total, 837 of 4,043 patients with MS with suspected/confirmed COVID-19 (20.7%) required hospitalization, and 130 of 4,310 (3.0%) died of COVID-19. Among suspected/confirmed patients, the highest hospitalization and mortality rates were in patients with no disease-modifying therapies (42.9% and 8.4%), followed by B cell–depleting agents (29.2% and 2.5%). CONCLUSION: Our study suggested that MS did not significantly increase the mortality rate from COVID-19. These data should be interpreted with caution as patients with MS are more likely female and younger compared with the general population where age and male sex seem to be risk factors for worse disease outcome.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the CNS, which is a leading cause of disability in young adults. Most patients with MS are treated with immunomodulatory medications, which increase the risk of opportunistic infection, infection-related hospitalization, and infection-related mortality rates. [1] [2] [3] [4] The first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was identified in Wuhan, China, on December 2019. After a rapid spread in China, new outbreaks occurred around almost all countries in the world. In March 2020, the World Health Organization (WHO) declared the outbreak of COVID-19 disease as a pandemic. 5 As of December 22, 2020, a total of 75,129,306 confirmed cases and 1,680,794 fatalities were reported to the WHO worldwide. 6 As coronavirus pandemic continues, a growing number of studies reported the clinical characteristics and outcomes of COVID-19 among patients with MS. However, there have been limited large observational studies investigating the symptoms, signs, complications, and outcome of COVID-19 in the MS population. The overall effects of COVID infection on MS and those on disease-modifying therapies (DMTs) remain unknown. To answer this question, we conducted this systematic review to bring together previous studies and provide an overall view of the published literature. The main goals of the current reviews are (1) to evaluate COVID infection outcomes in patients with MS (hospitalization/ mortality), (2) to evaluate the effects of DMTs on these outcomes, and (3) to determine the clinical features and presentation of COVID-19 in patients with MS. 

The inclusion criteria were as follows: (1) any type of studies including letters, case report, case series, cross-sectional, casecontrol, and cohort that reported COVID-19 among patients with MS and (2) written in English. The exclusion criteria were as follows: (1) not reporting outcome of patients with suspected or confirmed COVID-19, (2) preprint articles, (3) reviews, animal studies, hypothesis, and in vitro studies, and (4) articles reporting patients with Middle East respiratory syndrome-related coronavirus and SARS-CoV.

Two authors (M.B. and O.M.) independently screened, retrieved, and excluded reports. The reviewers screened the title and abstract of all retrieved articles. Both reviewers inspected the full text of all potential articles. Any disagreement over inclusion or exclusion of studies was resolved through feedback from a third reviewer (A.A.-S.).

Data extraction was conducted by 2 reviewers (M.B. and S.V.) separately. The data were extracted from eligible articles including fist author's name, first publication date, location of study, type of study, number of patients with confirmed/ suspected COVID-19, number of patients with positive PCR test, age, sex, Expanded Disability Status Scale (EDSS) score, disease duration, course of disease (relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndrome), DMT exposure, comorbidity (cardiovascular disease, diabetes mellitus, hypertension, chronic pulmonary diseases, malignancy, smoking status, obesity, and others), symptoms of COVID-19, and infection outcome (number of patients who hospitalized/number of death). This study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.

Two reviewers (M.B. and N.N.) independently rated the quality of studies using the Newcastle-Ottawa Scale quality assessments. 7 Based on studies design, different tools were Glossary COVID-19 = coronavirus disease 2019; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; MS = multiple sclerosis; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; WHO = World Health Organization.

used. Any disagreements were resolved by the senior reviewer (M.G.H.).

The primary outcome of the study was the assessment of clinical characteristics of COVID-19 among patients with MS. The secondary outcomes included assessment of hospitalization risk factors and proportion of patients required hospitalization, mortality rate, and relation to specific DMTs.

We used descriptive analysis to report the results. Descriptive statistics were reported as mean ± SD for continuous variables and frequency (%) for categorical variables. Aggregated data were weighted by the number of patients and then combined with individual data. The proportion of patients with MS hospitalized and death among patients with suspected/ confirmed COVID-19 with MS that reported in included studies were measured.

The PRISMA flowchart is shown in figure 1 . A total of 2,679 articles were initially identified. After removal of duplicates, 2,175 articles remained. In the end, 67 published articles consisting of 1,739 suspected/confirmed patients met the inclusion criteria. Among 3,138 conference abstracts, a total of 20 abstracts reporting 2,571 patients with MS with suspected/ confirmed COVID-19 were eligible for inclusion in the review. Totally, 87 studies consisting of 4,310 patients across 16 countries were included in our systematic review (figure e-1, links.lww.com/NXI/A476). The quality of evidence for each article is documented in table e-1 in appendix e-1.

The characteristics of each study are presented in table e-2, links.lww.com/NXI/A476. In terms of study design, 48 (45 published articles and 3 abstracts) studies were case reports/ series, 8,9, e12-e54,e62-e64 4 (2 articles and 2 abstracts) were pharmacovigilance case series, 10,11,e10,e11 18 (13 articles and 5 abstracts) were cross-sectional, 12-18,e2-e9,e59-e61 and 17 (7 articles and 10 abstracts) were cohort studies. 19-30,e1,e55-e58 Demographic and clinical characteristics of COVID-19 infection in patients are presented in table 1 and table e-3 in appendix e-1.

The main clinical characteristics of COVID-19 among patients with MS were fever (68.8%), cough (63.9%), fatigue/ asthenia (51.2%), shortness of breath (39.5%), headache 

The aim of the current study was to determine the characteristics and outcome of COVID-19 infection in patients with MS. In this review, all studies in the literature, which assessed COVID-19 among MS that met the review criteria, were included. In total, our study consisted of 87 studies including 4,310 patients with MS with suspected/confirmed COVID-19 infection.

The frequency of asymptomatic individuals in the general population is estimated up to 45% of all infected cases. 31 The low percentage (5.3%) of asymptomatic COVID-19 among patients with MS compared with the general population could be attributed to the fact that there are limited studies that have tested MS cohorts for antibodies to determine the rates of asymptomatic infection in this population. In total, 837 of 4,043 patients with MS with suspected/confirmed COVID-19 (20.7%) required hospitalization. The rate of hospitalization among patients with COVID-19 varies with age, sex, and presence of comorbidities. [32] [33] [34] [35] It is estimated that 1% of individuals younger than 20 years to about 20% of those aged 70 years or older would need hospitalization. 32 Hospitalization rates also vary according to the location of the study, race, and phase of pandemic ranging from 2.9 to 30% of all COVID-19 cases. [36] [37] [38] It seems that the hospitalization rates in patients with MS fall in the reported range for the general population; however, this has to be interpreted with caution as the demographic characteristics of patients with MS are generally younger and more female predominant than the general population, which should automatically put this cohort of patients at lower risks of hospitalization. Further studies are required to report outcomes after adjustment for variables that increase the rate of hospitalization in general population (e.g., age, sex, and race).

Among the included studies, 3 articles evaluated risk factors of hospitalization due to COVID-19 infection among the MS population. [19] [20] [21] Older age, male sex, and having at least 1 The COVID-19 mortality rate among all suspected and confirmed cases with MS was 3.0%. The WHO reports that as of 22 December 2020, a total of 2.2% patients died of COVID-19 worldwide. 6 The overall mortality rate of COVID-19 also differs between different countries, 1.8% in the United States, 2.2% in Europe, 4.6% in Iran, 2.6 in Brazil, and 2.8% in Chile. 6 The mortality rate is less than 1% in individuals aged 20-60 years and increases exponentially (more than 10%) after 60 years. [39] [40] [41] [42] Of 42 patients with MS who died of COVID-19, 8 (19.1%) were younger than 50 years and 21 (50.0%) patients were older than 60 years. Fortunately, the overall mortality rates in the MS cohort remain low at 3.0% in general, but these rates are not adjusted for age, sex, and presence of comorbidities.

There is a significant concern about the impact of different DMTs on susceptibility and outcome of patients with MS with COVID-19. Several guidelines and recommendations from expert groups have been published. [43] [44] [45] [46] General agreement exists that treatment of patients with MS with interferon and glatiramer acetate does not increase the risk of severe COVID-19, and interferon preparations may be even protective. There is concern that higher-efficacy medications including S1P modulators, B cell-depleting therapies, alemtuzumab, and cladribine may increase the risk of severe COVID-19 in patients with MS. In a study investigating outcome of COVID-19 among French patients with MS, DMT use was not independently associated with COVID-19 severity. 20 This was further supported by a study from New York, which showed no difference between hospitalized and non-hospitalized groups in the terms of DMT exposure. 19 Moreover, it has been suggested that B-cell depletion agents, particularly rituximab, 13, 16 and cladribine/alemtuzumab 23 may increase the risk of susceptibility to COVID-19. Evangelou et al. 47 showed that patients with high efficacy therapies were less likely to have COVID-19 compared with those with no DMT.

After pooling all patients and calculating the hospitalization and mortality rates for each DMT, the highest hospitalization rate was in patients with no DMT (42.9%), followed by B cell-depleting agents (29.2%), teriflunomide (20.6%), and fingolimod (14.7%). The highest mortality rate was in patients with no DMTs (8.4%), followed by B-cell depletion agents (2.5%), interferon (1.7%), teriflunomide (1.6%), and natalizumab (1.1%). Although it may appear that patients on no DMTs have higher mortality and hospitalization rates, however, this is confounded by the general practice that older patients or those with advanced terminal stages of MS are usually not treated with DMT as the risk outweighs the benefit in this group of patients. The hospitalization and mortality rates among patients receiving B cell depleting are 2 times higher than other DMTs. However, given prior reports of potential increased risk of COVID-19 in patients treated with B-cell therapies, the high hospitalization and mortality rates in this group should be studied in more details. It could be argued that high hospitalization rate of teriflunomide may be due to small number of reported patients. The hospitalization and mortality rates of DMTs therefore need to be interpreted with caution. Almost all patients with MS who died of COVID-19 were at high risk for developing severe COVID-19 because of age, comorbidity, or severe MS disability. Taken together, based on the current literature and small number of fatalities, it seems that MS may not dramatically increase the mortality rate from COVID-19.

Diagnosis of COVID-19 in 763 (of 2,173) patients with MS (35.1%) was confirmed by PCR; however we cannot determine the seropositivity among patients with MS because most suspected patients were not tested for the presence of antibodies. There are some similarities and differences between clinical features of COVID-19 reported by studies on MS and those described among the general population. 48, 49 Fever was the most common symptoms among patients with MS and the general population. [48] [49] [50] The prevalence of cough, shortness of breath/dyspnea in 63% and 39.5% among infected patients with MS with COVID-19 is broadly similar to those identified in other studies on the general population. 51 The pooled incidence of fatigue among all patients with COVID-19 is reported to be 46%, 49, 51 which is lower than of 51.2% reported in patients with MS. This difference may be explained by the fact that fatigue is one of the most common symptoms among patients with MS, and nearly 75% of the patients report fatigue during the disease and infections could worsen this symptom. 52 Our study has several limitations. First, a meta-analysis was not possible due to heterogeneity of studies. Second, it has been suggested that a significant proportion of individuals developed asymptomatic and mild COVID-19, but most patients in this study are symptomatic or admitted to a hospital. Although it remains unknown what percentage of patients with MS develop asymptomatic infection, it is possible that severe COVID-19 is overrepresented in the published literature, and the findings could not be extrapolated to the whole MS population. Third, most of the studies included are case reports/series or based on a small sample of participants. Fourth, without large multicentric studies and results from local and global COVID-19 data data sets, 53 the effect of DMTs on susceptibility and severity of COVID-19 remains unknown. Fifth, articles not published in English and not report clinical information of patients with COVID-19 were excluded, so some studies on the subject may not have been identified. Sixth, we cannot ascertain the incidence of COVID-19 among patients with MS. Population-based studies are needed to determine the true incidence of COVID-19 among patients with MS. Seventh, conference abstracts included inadequate data, and the validity of the results is questionable without proper peer review. However, inclusion of abstracts minimizes publication bias and provides more data that were not available in published format at the time of publication of this work.

In conclusion, our systematic review comprehensively detailed the demographic and clinical characteristics of patients with MS with COVID-19 published to date. Fortunately, the severity and mortality from COVID-19 in patients with MS does not seem to be significantly higher than the general population. However, further larger studies are needed to study this topic closer with adjustments for COVID-19 risk factors. Use of DMTs seems to be generally safe with no significant increased risk of poor COVID-19 outcomes; however, there may be a signal for B cell-depleting therapies slightly worsening COVID-19 infection.

No targeted funding reported.

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The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.